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Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms

  • Bodee Nutho
    Bodee Nutho
    Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
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  • Panupong Mahalapbutr
    Panupong Mahalapbutr
    Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
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    • , 
  • Kowit Hengphasatporn
    Kowit Hengphasatporn
    Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
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    • , 
  • Nawanwat Chainuwong Pattaranggoon
    Nawanwat Chainuwong Pattaranggoon
    Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
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  • Nattapon Simanon
    Nattapon Simanon
    Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
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  • Yasuteru Shigeta
    Yasuteru Shigeta
    Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
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    Orcidhttp://orcid.org/0000-0002-3219-6007
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  • Supot Hannongbua*
    Supot Hannongbua
    Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
    *Fax: +66 2 218-7603. Telephone: +66 2 218-7602. Email: [email protected]
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  • Thanyada Rungrotmongkol*
    Thanyada Rungrotmongkol
    Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
    Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
    *Fax: +66 2 218-5418. Telephone: +66 2 218-5426. Email: [email protected]
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    Orcidhttp://orcid.org/0000-0002-7402-3235
Cite this: Biochemistry 2020, 59, 18, 1769–1779
Publication Date (Web):April 15, 2020
https://doi.org/10.1021/acs.biochem.0c00160
Copyright © 2020 American Chemical Society
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Abstract

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Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.

  Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

In December 2019, there were many cases of patients reported to have a respiratory tract infection with severe pneumonia in Wuhan, China. It was found that these patients most likely had an epidemiological history related to a seafood market in that area of China.(1) However, a newly causative microbial infection cannot at first be identified in public databases. On the basis of whole genome sequencing, it was revealed that this microbial pathogen is a novel coronavirus, formally named 2019-nCoV, closely related to the bat severe acute respiratory syndrome (SARS)-like coronavirus, so-called SARS-CoV-2.(2,3) The World Health Organization (WHO) has officially confirmed the outbreak of 2019-nCoV on December 31, 2019, and eventually officially named it coronavirus disease 2019 or COVID-19. In general, coronaviruses are characterized as enveloped, positive-sense, single-stranded RNA viruses in the genus Coronavirus of the family Coronaviridae and can infect humans and several animals, including mammals and birds.(4−7) Nonetheless, some coronaviruses can potentially cause severe infection in patients such as the well-known outbreak of SARS-CoV in Guangdong, China,(8) and Middle East respiratory syndrome coronavirus (MERS-CoV) in many countries of the Middle East.(9) Likewise, COVID-19 has been confirmed to be transmitted from humans to humans and quickly spread in several countries throughout the world.(10)
SARS-CoV-2 is a betacoronavirus, like SARS-CoV and MERS-CoV, both of which have their origins in bats.(11) For the clinical symptoms, COVID-19 infection culminates in fatal pneumonia with the clinical presentation greatly resembling SARS-CoV infection.(1) Patients infected with SARS-CoV-2 might also develop acute respiratory distress syndrome, leading to a high rate of admission to intensive care units and ultimately death in severe cases.(7) After infection, patients presented mild to severe symptoms, including fever, cough, sore throat, rhinorrhea, severe pneumonia, and septic shock.(1,7)
To date, many companies and academic research groups around the world have focused on searching for and developing a specific vaccine or antiviral drug to prevent or control emerging SARS-CoV-2 infections (e.g., vaccine, monoclonal antibodies, and small-molecule drugs). However, these options need several months to years for their development. Because of the urgent need to alleviate the COVID-19 pandemic, the use of repurposed existing antiviral drugs approved for treatment of other viral infections such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and influenza is somewhat promising,(12) based on previous successes of the therapeutic treatment with two relevant human coronaviruses, SARS-CoV and MERS-CoV. According to numerous previous studies,(1,7,13−16) the nonstructural protein of coronavirus, in particular, main proteases or 3C-like proteases (3CLpro), is considered an attractive drug target for the treatment of coronavirus infection. The role of this protease involves the proteolytic processing of the replicase polyprotein and is crucial for viral replication and maturation.(17) Moreover, 3CLpro has a similar common cleavage site among coronaviruses.(18) The sequence alignment of SARS-CoV-2 3CLpro (see Figure S1) shows that the SARS-CoV-2 proteinase is highly conserved compared to that of SARS-CoV with a 96.1% sequence identity.
A combination of the two approved drugs for HIV infection, lopinavir and ritonavir (KALETRA), has been reported to be active toward SARS and MERS.(14,19) Both anti-HIV drugs were initially purposed to inhibit 3CLpro of SARS-CoV and MERS-CoV, and they appeared to be related to clinical benefits of patients with SARS in a nonrandomized open-label trial.(17) Although ritonavir is a protease inhibitor, it is generally used to inhibit cytochrome P450 3A4 and markedly increases the plasma concentrations of other protease inhibitors.(20) Nevertheless, whether HIV protease inhibitors could effectively target SARS-CoV-2 3CLpro is under debate. This is based on the fact that HIV protease is from the aspartic protease family, whereas SARS-CoV-2 3CLpro belongs to the cysteine protease family. Previously, a theoretical study of the molecular interaction of lopinavir and ritonavir with 3CLpro of SARS-CoV suggested that these two drugs could bind well at the substrate-binding pocket of SARS-CoV 3CLpro.(15) To date, the three-dimensional structure of SARS-CoV-2 3CLpro in a complex with lopinavir and ritonavir has not been reported. Thus, in our study, we aimed to investigate the binding interactions of lopinavir and ritonavir with the SARS-CoV-2 proteinase using both molecular modeling and quantum chemical methods. It is our hope that this information can be useful for the future design or development of more specific inhibitors for the treatment of human coronaviruses.

Computational Details

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System Preparation

The co-crystal structure of homodimeric SARS-CoV-2 3CLpro in complex with a peptidomimetic inhibitor [N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-n-1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-l-leucinamide] was retrieved from the RSCB Protein Data Bank (PDB entry 6LU7).(21) Note that each moiety of the peptidomimetic inhibitor is associated with the -P5-P4-P3-P2-P1-P1′- positions of the 3CLpro cleavage site (Figure 1A). To generate the models of SARS-CoV-2 3CLpro with lopinavir and ritonavir bound to protomer A, the positions of the original peptidelike inhibitor were changed to the corresponding drug for each P position (Figure 1B,C). This modification was performed according to the similar orientation with the template inhibitor using the small molecules tool implemented in Accelrys Discovery Studio 2.5 (Accelrys Inc.). The protonation states of all ionizable amino acids were assigned at pH 7.4 using the H++ web server,(22) except for the catalytic residue H41 that was set as the neutral form with a protonated delta position (HID type of AMBER format) in accordance with the common reaction mechanism of cysteine protease.(23) The chemical structures of lopinavir (ZINC3951740) and ritonavir (ZINC3944422) were downloaded from the ZINC15 database.(24) The electrostatic potential (ESP) charges of both ligands were calculated with the HF/6-31G* level of theory using the Gaussian09 program.(25) The antechamber and parmchk modules of AMBER16 were used to generate the restrained ESP charges and missing parameters of the two drugs, respectively. The bonded and nonbonded parameters for the protein and ligand were treated with the AMBER ff14SB force field(26) and generalized AMBER force field version 2 (GAFF2),(27) accordingly. Missing hydrogen atoms were added using the LEaP module implemented in AMBER16. Afterward, the TIP3P water model(28) was used to solvate each system with a minimum distance of 10 Å between the protein surface and the solvation box edge, and the box dimensions were set to approximately 114 Å × 97 Å × 92 Å. The sodium ions were then randomly added to neutralize the simulated systems. The added hydrogen atoms and water molecules were minimized using 500 steps of steepest descent (SD) followed by 1500 steps of conjugated gradient (CG) methods before running the MD simulations, while the rest of the molecules were held fixed. Then, the protein and ligand were minimized by SD (500 iterations) and CG (1500 iterations) methods with constrained solvent molecules. Finally, the whole complex was fully minimized using the same procedure.

Figure 1

Figure 1. (A) Three-dimensional structure of the peptidelike inhibitor binding to the active site of the SARS-CoV-2 3CLpro homodimer (PDB entry 6LU7) in one asymmetric unit (A, yellow; B, cyan). Protomers are shown as ribbons, and the inhibitor is shown as an orange ball and stick model. Chemical structures of (B) lopinavir and (C) ritonavir, where the atomic labels are also given.

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Molecular Dynamics Simulations

Each system was simulated under the periodic boundary condition with the isothermal–isobaric (NPT) scheme, as previously described.(29−32) Briefly, a cutoff distance for nonbonded interactions was set to 10 Å, while the particle mesh Ewald summation method(33) was employed to treat the electrostatic interactions. The SHAKE algorithm(34) was used to constrain all covalent bonds involving hydrogen atoms. A 2 fs simulation time step was used throughout the MD simulation. The temperature and pressure were controlled by the Langevin thermostat(35) with a collision frequency of 2 ps–1 and the Berendsen barostat(36) with a pressure-relaxation time of 1 ps. For the heating step, each simulated system was gradually heated from 10 to 310 K for 200 ps with a harmonic positional restraint of 30.0 kcal mol–1 Å–2 applied to the Cα atoms of the protein. To equilibrate the system, each complex was then subjected to four steps of restrained MD simulations at 310 K with harmonic restraints of 30, 20, 10, and 5 kcal mol–1 Å–2 for 1300 ps in total and another 200 ps without any restraint. Subsequently, the entire system was simulated under the NPT ensemble (310 K and 1 atm) until reaching 100 ns. The MD trajectories were saved every 10 ps. The calculations in terms of the root-mean-square displacement (RMSD), the number of protein–drug hydrogen bonds (# H-bonds), and the number of atomic contacts (# atom contacts) with the drug molecule were used to verify the stability of all investigated models as well as the structural features of each complex. The H-bond interactions were calculated using two criteria: (i) distance between the hydrogen donor (HD) and acceptor (HA) of ≤3.5 Å and (ii) HD–H···HA angle of ≥150°. The # atom contacts were counted from the number of 3CLpro atoms within 3.5 Å of each drug. To evaluate the binding affinity and the key binding residues involved in ligand binding of the protein–ligand complexes, the total binding free energy (ΔGbind) and per-residue decomposition free energy (ΔGbindresidue) calculations based on molecular mechanics/Poisson–Boltzmann (generalized Born) surface area [MM/PB(GB)SA] methods were performed on 100 MD snapshots extracted from the last 20 ns of the MD production phase. It should be noted that the protein–ligand interactions and the binding free energies were carried out using the CPPTRAJ(37) and MMPBSA.py(38) modules of AMBER16, respectively. Furthermore, the intermolecular interactions between the drug and its binding residues at the atomic level were described by pair interaction energy decomposition analysis (PIEDA) based on the fragment molecular orbital (FMO) method at the second-order Møller–Plesset perturbation energy and the 6-31G* level of theory (FMO-MP2/6-31G*) using GAMESS.(39) The solvation effect was also treated with a polarizable continuum model (PCM). The paired interaction energy (ΔEijPIEDA) involved in ligand binding was evaluated by a summation of the electrostatic (EijES), dispersion (EijDI), charge transfer (EijCT+mix), and charge exchange (EijEX) energies, as well as PCM solvation (GsolPCM), using the following equation:(40−42)

Results and Discussion

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System Stability

The stability of each simulated model was determined by calculating the all-atom RMSD for the drug–3CLpro complex, the number of intermolecular H-bonds (# H-bonds), and the number of atom contacts (# atom contacts) with the drug molecule versus the simulation time. As shown in Figure 2, the RMSD values of both lopinavir and ritonavir systems continuously increased in the first 40 ns and then maintained at a fluctuation of ∼2.0 Å until the end of the simulation time, as supported by a high fluctuation of # H-bonds and # atom contacts in the first 40 ns. It should be noted that the # H-bonds and # atom contacts of the ritonavir system (# H-bonds of 3 ± 1 and # atom contacts of 19 ± 4 over the last 20 ns) were higher than those of the lopinavir model (# H-bonds of 2 ± 1 and # atom contacts of 14 ± 4), suggesting that ritonavir was more susceptible to SARS-CoV-2 3CLpro (discussed in more detail below). In this work, the MD trajectories from 80 to 100 ns were thus extracted for further analysis in terms of (i) the binding affinity between lopinavir or ritonavir and SARS-CoV-2 3CLpro, (ii) key binding residues involved in drug binding, (iii) protein–drug H-bonding, and (iv) water accessibility at the enzyme active site.

Figure 2

Figure 2. All-atom RMSD, # H-bonds, and # atom contacts of lopinavir (left) and ritonavir (right) in complex with SARS-CoV-2 3CLpro plotted along the 100 ns MD simulation.

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Predicted Inhibitory Efficiency

The susceptibility of lopinavir and ritonavir to SARS-CoV-2 3CLpro was estimated using the MM/PB(GB)SA approach on 100 snapshots extracted from the last 20 ns of simulation. Note that the MM/PBSA and MM/GBSA results in Table 1 provided a similar trend in the binding free energy predictions.
Table 1. ΔGbind Values (kilocalories per mole) of Lopinavir and Ritonavir in Complex with SARS-CoV-2 3CLpro Calculated by the MM/PB(GB)SA Methoda
energy componentlopinavirritonavir
Gas Term
ΔEvdW–50.29 ± 0.62–74.09 ± 0.50
ΔEele–19.68 ± 0.50–23.35 ± 0.56
ΔEMM–69.97 ± 0.87–97.44 ± 0.60
–TΔS22.47 ± 1.7929.46 ± 1.77
Solvation Term
PBSA
ΔGsol(PBSA)ele41.64 ± 0.5359.47 ± 0.46
ΔGsol(PBSA)nonpolar–5.03 ± 0.04–6.42 ± 0.02
ΔGsol(PBSA)36.61 ± 0.5153.04 ± 0.45
GBSA
ΔGsol(GBSA)ele40.11 ± 0.4048.72 ± 0.37
ΔGsol(GBSA)nonpolar–6.43 ± 0.07–8.53 ± 0.04
ΔGsol(GBSA)33.67 ± 0.3740.19 ± 0.37
Binding Free Energy
ΔGbind(MM/PBSA)–10.89 ± 1.89–14.93 ± 1.83
ΔGbind(MM/GBSA)–13.83 ± 1.91–27.78 ± 1.82
a

Data are shown as means ± the standard error of the mean (SEM).

According to the molecular mechanics (ΔEMM) calculations, we found that van der Waals (vdW) interaction is the main force inducing molecular complexation with SARS-CoV-2 3CLpro of both lopinavir (ΔEvdW of −50.29 ± 0.62 kcal/mol) and ritonavir (−74.09 ± 0.50 kcal/mol) and is ∼2–3-fold stronger than the electrostatic attraction (ΔEele values of −19.68 ± 0.50 and −23.35 ± 0.56 kcal/mol, respectively). This finding was in a good agreement with the ΔEMM results of (i) these two anti-HIV drugs in complex with SARS-CoV 3CLpro(15) and (ii) darunavir and amprenavir binding to the HIV-1 protease.(43) Taken together with the solvation effect and entropic term, the binding affinity (ΔGbind) of ritonavir with SARS-CoV-2 3CLpro (−14.93 ± 1.83 and −27.78 ± 1.82 kcal/mol taken from the MM/PBSA and MM/GBSA methods, respectively) was relatively higher than that of another drug (−10.89 ± 1.89 and −13.83 ± 1.91 kcal/mol, respectively). The predicted results suggested that ritonavir may have an ∼1.4–2.0-fold greater inhibitory efficiency than lopinavir on the focused target; however, it should be noted that this drug can clinically also boost the lopinavir efficacy in the fight against COVID-19.

Key Residues for the Repurposed HIV Drug to Combat COVID-19

To evaluate the key residues involved in anti-HIV drug binding at the active site of SARS-CoV-2 3CLpro, the ΔGbindresidue calculation based on the MM/GBSA method was performed. The total energy contribution from each residue associated with drug binding of both complexes is plotted in Figure 3, and the drug orientation in the enzyme active site is illustrated in the right panel, in which the contributing amino acids are colored according to their ΔGbindresidue values. It is important to note that only residues exhibiting an energy stabilization of ≤−1.0 kcal/mol were taken into account.

Figure 3

Figure 3. ΔGbindresidue values of lopinavir (top) and ritonavir (bottom) in complex with SARS-CoV-2 3CLpro. The contributing residues involved in ligand binding are colored according to their ΔGbindresidue values, where the highest to lowest free energies are shaded from gray to blue, respectively.

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The obtained results revealed that there were four (M49, M165, P168, and Q189) and nine residues (L27, H41, M49, F140, N142, G143, H164, M165, and E166) that were important for the binding of lopinavir and ritonavir, respectively. The more strongly contributing residues found in the SARS-CoV-2 3CLpro–ritonavir complex were in accordance with the results mentioned above (Figure 2 and Table 1). Similarly, it was reported that the SARS-CoV 3CLpro residues (i) M49 and M165 and (ii) E166 strongly stabilized PJ207, a quinazoline-containing compound, mainly through hydrophobic interaction and H-bond formation, respectively.(44) In line with this finding, our ΔGbindresidue calculation showed that the phenyl ring at the P1 position of lopinavir and the thiazole ring at the P2 position of ritonavir were inserted into the S2 pocket of SARS-CoV-2 3CLpro, forming hydrophobic contacts with residues M49 and M165 (Figure 3), and the O1 atom of ritonavir was stabilized by the -NH group of E166 via H-bond formation (Figure 6, discussed below). It is of note that only ritonavir could interact with the catalytic residue H41(45) and the oxyanion hole residues N142 and G143(46) (ΔGbindresidue of −1.4 kcal/mol for each residue), suggesting that the molecular structure of ritonavir fitted well within the active site of SARS-CoV-2 3CLpro. The obtained information was supported by the well-aligned structures of ritonavir over the last 20 ns simulation (Figure 4), whereas a large fluctuation of the P2′ site was detected in lopinavir.

Figure 4

Figure 4. Superimposed structures over the 20 snapshots of (A) lopinavir and (B) ritonavir in complex with SARS-CoV-2 3CLpro derived from the last 20 ns of MD simulations.

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In terms of the contribution from the electrostatic (ΔEele + ΔGpolar, black line) and vdW (ΔEvdW + ΔGnonpolar, red line) energies from each residue, it can be seen from Figure 5 that the main energy contribution for stabilizing the HIV-1 protease inhibitors lopinavir and ritonavir was the vdW energy (≲−4.0 kcal/mol), especially for residues M49, M165, and Q189, whereas the electrostatic contribution was observed in the range of approximately −1.0 to 2.0 kcal/mol as related to the ΔEMM calculations (see Table 1). However, there is a common concern about the drawbacks of the molecular mechanics calculations, in particular electronic properties. The FMO-MP2/PCM/6-31G* calculation was additionally performed on the last snapshot of each complex to investigate the protein–drug interactions at the enzyme active site. The advantage of this method is known to include the electron correlation, which trustworthily describes the hydrophobic effect and hydrogen bond interaction between the ligand and individual residue.(40,47,48)Figure 6 highlights that residue Q189 dramatically stabilized lopinavir (−37.3 kcal/mol) mainly through electrostatic, dispersion, and charge transfer contributions (−28.1, −18.3, and −8.1 kcal/mol, respectively), whereas residues H41, A46, M49, E166, L167, L187, A191, and A193 had moderately stabilizing effects with energy values in the range of approximately −5 to −10 kcal/mol via dispersion and/or electrostatic interactions. In contrast, there were four essential amino acids (i.e., N142, M165, E166, and Q189) contributing to ritonavir binding with an energy stabilization of approximately −12 to −20 kcal/mol, whereas residues G143, S144, C145, and D187 showed less energy stabilization of approximately −5 to −7 kcal/mol, most likely through dispersion and electrostatic interactions, except for residue E166, for which the impact of the solvation effect was predominantly found on the two drugs binding to SARS-CoV-2 3CLpro.

Figure 5

Figure 5. Electrostatic (ΔEele + ΔGpolar, black line) and vdW (ΔEvdW + ΔGnonpolar, red line) energy contributions from each residue of SARS-CoV-2 3CLpro to the binding of lopinavir (top) and ritonavir (bottom).

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Figure 6

Figure 6. Pair interaction energy decomposition analysis (PIEDA) of lopinavir (top) and ritonavir (bottom) interacting with individual residues in the binding pocket of SARS-CoV-2 3CLpro based on FMO-MP2/PCM/6-31G* calculation.

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As compared to the recently reported potent α-ketoamide inhibitor (13b) bound to SARS-CoV-2 3CLpro,(49) the anti-HIV drugs lopinavir and ritonavir lack (i) the P3 moiety, (ii) an α-ketoamide group located between positions P1 and P1′, and (iii) polar moieties on the phenyl ring in the P1 region. However, the phenyl ring at the P1′ site of both HIV-1 protease inhibitors and 13b remains the same, and the P2 (larger and more hydrophilic than 13b) and P2′ (found only in HIV-1 protease inhibitors) regions of lopinavir and ritonavir strongly interacted with SARS-CoV-2 3CLpro at the S2 and S2′ pockets, respectively (Figure 3). Accordingly, on the basis of this evidence, we proposed a rational design of novel protease inhibitor(s) derived from lopinavir and ritonavir to enhance the binding efficiency with SARS-CoV-2 3CLpro as follows: (i) changing the phenyl ring in the P1 region to the γ-lactam ring to increase the extent of H-bond formation with residues F140, H163, and E166, (ii) introducing P3 polar moieties (e.g., pyridone ring) to form H-bonds with the negatively charged E166, and (iii) adding the reactive α-ketoamide group located between positions P1 and P1′ to covalently bond with the catalytic residue C145, as depicted in Figure 7.

Figure 7

Figure 7. Rational drug design of the SARS-CoV-2 3CLpro inhibitors. Note that the green dashed line indicates H-bond formation.

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Protein–Drug Hydrogen Bonding

Although the protein–drug interactions were primarily contributed by the vdW interactions, the formation of H-bonds between both anti-HIV drugs and their surrounding residues in the active site of SARS-CoV-2 3CLpro could be an important factor in the inhibition of this targeted enzyme. To monitor such interaction, the percentages of H-bond occupations are plotted in Figure 8, whereas the representative structures determined from the last MD snapshot are depicted in Figure 9. As expected, H-bond formation (three to four H-bonds) between the drugs and the surrounding residues inside the active site of SARS-CoV-2 3CLpro was observed. In the case of lopinavir, there were three H-bonds: (i) O1(P2 site)···H–NE2(Q189) at 70.6%, (ii) O(T190)···H–N1(P2 site) at 14.8%, and (iii) OE1(Q189)···H–N4(P1 site) at 83.9%. Meanwhile, four H-bonds were detected in the ritonavir complex: (i) O1(P2 site)···H–N(E166) at 65.6%, (ii) O(H164)···H–N4(P1 site) at 72.6%, (iii) OD1(N142)···H–N5(P1′ site) at 17.3%, and (iv) O3(P1′ site)···H–N(G143) at 85.6%. It can be noticed that the importance of residues E166 and Q189 also agreed well with the reported binding of such HIV-1 protease inhibitors to SARS-CoV.(15) Notably, ritonavir showed a slightly higher level of H-bond formation with 3CLpro, and its P1′ site was stabilized by the oxyanion hole residues N142 and G143.

Figure 8

Figure 8. Percentage of H-bond occupation of SARS-CoV-2 3CLpro that contributed to the binding of lopinavir (top) and ritonavir (bottom).

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Figure 9

Figure 9. Binding patterns of (A) lopinavir and (B) ritonavir in complex with SARS-CoV-2 3CLpro demonstrated from the last MD snapshot. Black dashed lines represent H-bonds.

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Solvent Accessibility in the 3CLpro Active Site

As the active site of SARS-CoV-2 3CLpro is located near the solvent-exposed area, water molecules might play a role in stabilizing protein–ligand interactions. To characterize the effect of water accessibility at the 3CLpro active site, the solvent-accessible surface area (SASA) (Figure 10) calculations were performed on the residues within 4 Å of each anti-HIV drug. Moreover, the radial distribution function (RDF) (Figure 11) of water oxygens toward all heteroatoms of lopinavir and ritonavir was used to verify the number of water molecules approaching the ligands.

Figure 10

Figure 10. (A) SARS-CoV-2 3CLpro homodimer, in which chain A with a drug bound and chain B without a drug bound are shown in shades of yellow and blue, respectively. Note that the amino acid residues within 4 Å (stick model) of the ligand (ball and stick representation) were used for SASA calculations. (B) SASA plots along the simulation time of the two studied systems. (C) Average SASAs of lopinavir and ritonavir systems.

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Figure 11

Figure 11. Radial distribution functions, g(r), of the water oxygen atom and integration numbers, n(r), up to the first minimum around the heteroatoms of (A) lopinavir and (B) ritonavir (see Figure 1 for definitions) in complex with SARS-CoV-2 3CLpro. H-Bond water networks of the drug, bridging water, and SARS-CoV-2 3CLpro residue are shown as black dashed lines.

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Our complex model of the SARS-CoV-2 3CLpro homodimer contained the anti-HIV drugs binding only to protomer A. It can be seen from Figure 10 that the SASAs for protomer B (blue) were 883.81 ± 75.24 and 918.15 ± 110.03 Å2 for the lopinavir and ritonavir systems, respectively. Upon molecular complexation in protomer A (yellow), the SASAs of both lopinavir (500.21 ± 67.38 Å2) and ritonavir (451.60 ± 61.62 Å2) systems dramatically decreased in a manner similar to those of other studies.(50−52) By considering the RDF results, we found that the first peak at ∼3 Å of the lopinavir system (up to ∼2) was slightly higher than that of the ritonavir system (up to ∼1.4), indicating that accessible water molecules were more pronounced in the SARS-CoV-2 3CLpro–lopinavir complex. As the H-bond water network, protein···water···drug, also plays a role in stabilizing the protein–ligand complex,(53) we further investigated the H-bond water bridges around the heteroatoms of both ligands using the same structural criteria of H-bonds described elsewhere. The obtained results demonstrated that there was only one bridging water coordinating with (i) lopinavir (O2) and E166 as well as (ii) ritonavir (O4) and N142 with a very low percentage of occupancy (∼5–13%), suggesting that the bridging water did not make a significant contribution to mediating the H-bond network of protein–ligand binding.

Conclusions

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In this work, the binding pattern and susceptibility of the two HIV-1 protease inhibitors lopinavir and ritonavir in complex with SARS-CoV-2 3CLpro were fully revealed by all-atom MD simulations, binding free energy estimation, and PIEDA based on the MM/PB(GB)SA and FMO-MP2/PCM/6-31G* calculations, respectively. According to ΔGbind prediction, the susceptibility against SARS-CoV-2 3CLpro of ritonavir was somewhat higher than that of lopinavir, supported by energy stabilization from individual residues that resulted from both methods: (i) M49, M165, P168, and Q189 from MM/GBSA for lopinavir and L27, H41, M49, F140, N142, G143, H164, M165, and E166 from MM/GBSA for ritonavir and (ii) H41, A46, M49, E166, L167, L187, Q189, A191, and A193 from FMO-MP2/PCM/6-31G* for lopinavir and N142, G143, S144, C145, M165, E166, D187, and Q189 from FMO-MP2/PCM/6-31G* for ritonavir. In addition, the oxyanion hole residues N142 and G143 were found to interact with ritonavir via hydrogen bonds. From the FMO-MP2/PCM/6-31G* data, the electrostatics, dispersion, and charge transfer were considered as the important interactions for drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19 and how fundamental knowledge at the atomic level could also be helpful for the further design or development of more specific inhibitors in treating human coronaviruses.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biochem.0c00160.

  • Amino acid sequences and structural comparison (PDF)

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Author Information

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  • Corresponding Authors
    • Supot Hannongbua - Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;  Email: [email protected]
    • Thanyada Rungrotmongkol - Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;  Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand;  Orcidhttp://orcid.org/0000-0002-7402-3235;  Email: [email protected]
  • Authors
    • Bodee Nutho - Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
    • Panupong Mahalapbutr - Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
    • Kowit Hengphasatporn - Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
    • Nawanwat Chainuwong Pattaranggoon - Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
    • Nattapon Simanon - Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
    • Yasuteru Shigeta - Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan;  Orcidhttp://orcid.org/0000-0002-3219-6007
  • Author Contributions

    B.N. and P.M. contributed equally to this work.

  • Funding

    The Second Century Fund (C2F), Chulalongkorn University (CU) is acknowledged for B.N. and P.M. (postdoctoral fellowship) and N.C.P. (Ph.D. scholarship). NSTDA Supercomputer Center (ThaiSC) is acknowledged for facilities and computing resources.

  • Notes

    The authors declare no competing financial interest.

References

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    de Groot, R. J., Baker, S. C., Baric, R. S., Brown, C. S., Drosten, C., Enjuanes, L., Fouchier, R. A. M., Galiano, M., Gorbalenya, A. E., Memish, Z. A., Perlman, S., Poon, L. L. M., Snijder, E. J., Stephens, G. M., Woo, P. C. Y., Zaki, A. M., Zambon, M., and Ziebuhr, J. (2013) Middle east respiratory syndrome coronavirus (MERS-CoV): Announcement of the coronavirus study group. J. Virol. 87 (14), 7790– 7792,  DOI: 10.1128/JVI.01244-13
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    Middle east respiratory syndrome coronavirus (MERS-CoV): announcement of the coronavirus study group
    de Groot, Raoul J.; Baker, Susan C.; Baric, Ralph S.; Brown, Caroline S.; Drosten, Christian; Enjuanes, Luis; Fouchier, Ron A. M.; Galiano, Monica; Gorbalenya, Alexander E.; Memish, Ziad A.; Perlman, Stanley; Poon, Leo L. M.; Snijder, Eric J.; Stephens, Gwen M.; Woo, Patrick C. Y.; Zaki, Ali M.; Zambon, Maria; Ziebuhr, John
    Journal of Virology (2013), 87 (14), 7790-7792CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    A review. A brief review including epidemiol., description, and consensus name for Middle east respiratory syndrome coronavirus (MERS-CoV).
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  10. 10
    Chan, J. F. W., Yuan, S., Kok, K. H., Chu, K. K. W., Yang, H., Xing, J., Liu, F., Yip, J., Poon, C. C. Y., Tsoi, R. W. S., Lo, H. W., Chan, S. K. F., Poon, K. H., Chan, V. K. M., Ip, W. M., Cai, J. D., Cheng, J. P., Chen, V. C. C., Hui, C. K.-M., To, K. K.-W., and Yuen, K. Y. (2020) A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395, 514,  DOI: 10.1016/S0140-6736(20)30154-9
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    A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster
    Chan, Jasper Fuk-Woo; Yuan, Shuofeng; Kok, Kin-Hang; To, Kelvin Kai-Wang; Chu, Hin; Yang, Jin; Xing, Fanfan; Liu, Jieling; Yip, Cyril Chik-Yan; Poon, Rosana Wing-Shan; Tsoi, Hoi-Wah; Lo, Simon Kam-Fai; Chan, Kwok-Hung; Poon, Vincent Kwok-Man; Chan, Wan-Mui; Ip, Jonathan Daniel; Cai, Jian-Piao; Cheng, Vincent Chi-Chung; Chen, Honglin; Hui, Christopher Kim-Ming; Yuen, Kwok-Yung
    Lancet (2020), 395 (10223), 514-523CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    An ongoing outbreak of pneumonia assocd. with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geog. linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. In this study, we report the epidemiol., clin., lab., radiol., and microbiol. findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an addnl. family member who did not travel to Wuhan. Phylogenetic anal. of genetic sequences from these patients were done. From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Addnl., one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiol. ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiol. ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were neg. for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR pos. for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic anal. of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiratory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travelers in other geog. regions. The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Com. Assocn. South China Microbiol. Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).
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  11. 11
    Su, S., Wong, G., Shi, W., Liu, J., Lai, A. C. K., Zhou, J., Liu, W., Bi, Y., and Gao, G. F. (2016) Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 24 (6), 490– 502,  DOI: 10.1016/j.tim.2016.03.003
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    Epidemiology, genetic recombination, and pathogenesis of coronaviruses
    Su, Shuo; Wong, Gary; Shi, Weifeng; Liu, Jun; Lai, Alexander C. K.; Zhou, Jiyong; Liu, Wenjun; Bi, Yuhai; Gao, George F.
    Trends in Microbiology (2016), 24 (6), 490-502CODEN: TRMIEA; ISSN:0966-842X. (Elsevier Ltd.)
    A review. Human coronaviruses (HCoVs) were first described in the 1960s for patients with the common cold. Since then, more HCoVs have been discovered, including those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), two pathogens that, upon infection, can cause fatal respiratory disease in humans. It was recently discovered that dromedary camels in Saudi Arabia harbor three different HCoV species, including a dominant MERS HCoV lineage that was responsible for the outbreaks in the Middle East and South Korea during 2015. In this review we aim to compare and contrast the different HCoVs with regard to epidemiol. and pathogenesis, in addn. to the virus evolution and recombination events which have, on occasion, resulted in outbreaks amongst humans.
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  12. 12
    De Clercq, E. and Li, G. (2016) Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 29 (3), 695– 747,  DOI: 10.1128/CMR.00102-15
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    Approved Antiviral Drugs over the Past 50 Years
    De Clercq Erik; Li Guangdi
    Clinical microbiology reviews (2016), 29 (3), 695-747 ISSN:.
    Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.
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    Kaplan, S. S. and Hicks, C. B. (2005) Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection. Expert Opin. Pharmacother. 6 (9), 1573– 1585,  DOI: 10.1517/14656566.6.9.1573
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    Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection
    Kaplan, Susan S.; Hicks, Charles B.
    Expert Opinion on Pharmacotherapy (2005), 6 (9), 1573-1585CODEN: EOPHF7; ISSN:1465-6566. (Ashley Publications Ltd.)
    A review. The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clin. value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favorable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clin. trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clin. trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.
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    Chu, C. M., Cheng, V. C. C., Hung, I. F. N., Wong, M. M. L., Chan, K. H., Chan, K. S., Kao, R. Y. T., Poon, L. L. M., Wong, C. L. P., Guan, Y., Peiris, J. S. M., and Yuen, K. Y. (2004) Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 59 (3), 252– 256,  DOI: 10.1136/thorax.2003.012658
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    14
    Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings
    Chu C M; Cheng V C C; Hung I F N; Wong M M L; Chan K H; Chan K S; Kao R Y T; Poon L L M; Wong C L P; Guan Y; Peiris J S M; Yuen K Y
    Thorax (2004), 59 (3), 252-6 ISSN:0040-6376.
    BACKGROUND: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. METHODS: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. RESULTS: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 micro g/ml and 50 micro g/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls-both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. CONCLUSIONS: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.
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    Nukoolkarn, V., Lee, V. S., Malaisree, M., Aruksakulwong, O., and Hannongbua, S. (2008) Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors. J. Theor. Biol. 254 (4), 861– 867,  DOI: 10.1016/j.jtbi.2008.07.030
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    Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CLpro inhibitors
    Nukoolkarn, Veena; Lee, Vannajan Sanghiran; Malaisree, Maturos; Aruksakulwong, Ornjira; Hannongbua, Supot
    Journal of Theoretical Biology (2008), 254 (4), 861-867CODEN: JTBIAP; ISSN:0022-5193. (Elsevier Ltd.)
    Since the emergence of the severe acute respiratory syndrome (SARS) to date, neither an effective antiviral drug nor a vaccine against SARS is available. However, it was found that a mixt. of two HIV-1 proteinase inhibitors, lopinavir and ritonavir, exhibited some signs of effectiveness against the SARS virus. To understand the fine details of the mol. interactions between these proteinase inhibitors and the SARS virus via complexation, mol. dynamics simulations were carried out for the SARS-CoV 3CLpro free enzyme (free SARS) and its complexes with lopinavir (SARS-LPV) and ritonavir (SARS-RTV). The results show that flap closing was clearly obsd. when the inhibitors bind to the active site of SARS-CoV 3CLpro. The binding affinities of LPV and RTV to SARS-CoV 3CLpro do not show any significant difference. In addn., six hydrogen bonds were detected in the SARS-LPV system, while seven hydrogen bonds were found in SARS-RTV complex.
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    Liu, X. and Wang, X.-J. (2020) Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J. Genet. Genomics 47, 119,  DOI: 10.1016/j.jgg.2020.02.001
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    Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines
    Liu Xin; Wang Xiu-Jie
    Journal of genetics and genomics = Yi chuan xue bao (2020), 47 (2), 119-121 ISSN:1673-8527.
    There is no expanded citation for this reference.
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    Zumla, A., Chan, J. F. W., Azhar, E. I., Hui, D. S. C., and Yuen, K. Y. (2016) Coronaviruses-drug discovery and therapeutic options. Nat. Rev. Drug Discovery 15 (5), 327– 347,  DOI: 10.1038/nrd.2015.37
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    Coronaviruses - drug discovery and therapeutic options
    Zumla, Alimuddin; Chan, Jasper F. W.; Azhar, Esam I.; Hui, David S. C.; Yuen, Kwok-Yung
    Nature Reviews Drug Discovery (2016), 15 (5), 327-347CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, resp., have received global attention over the past 12 years owing to their ability to cause community and health-care-assocd. outbreaks of severe infections in human populations. These two viruses pose major challenges to clin. management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiol., virol., clin. features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.
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    Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R., and Hilgenfeld, R. (2003) Coronavirus main proteinase (3CLpro) Structure: Basis for design of anti-SARS drugs. Science 300 (5626), 1763– 1767,  DOI: 10.1126/science.1085658
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    Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs
    Anand, Kanchan; Ziebuhr, John; Wadhwani, Parvesh; Mesters, Jeroen R.; Hilgenfeld, Rolf
    Science (Washington, DC, United States) (2003), 300 (5626), 1763-1767CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (Mpro, also called 3CLpro), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. The authors detd. crystal structures for human coronavirus (strain 229E) Mpro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] Mpro, and the authors constructed a homol. model for SARS coronavirus (SARS-CoV) Mpro. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV Mpro-mediated cleavage of a TGEV Mpro substrate. Mol. modeling suggests that available rhinovirus 3Cpro inhibitors may be modified to make them useful for treating SARS.
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    Arabi, Y. M., Alothman, A., Balkhy, H. H., Al-Dawood, A., AlJohani, S., Al Harbi, S., Kojan, S., Al Jeraisy, M., Deeb, A. M., Assiri, A. M., Al-Hameed, F., AlSaedi, A., Mandourah, Y., Almekhlafi, G. A., Sherbeeni, N. M., Elzein, F. E., Memon, J., Taha, Y., Almotairi, A., Maghrabi, K. A., Qushmaq, I., Al Bshabshe, A., Kharaba, A., Shalhoub, S., Jose, J., Fowler, R. A., Hayden, F. G., Hussein, M. A., Martin, G. S., Schoenfeld, D. A., Walmsley, S. L., Carson, S., Harbi, S. A., Jeraisy, M. A., Muhaidib, M. A., Musharaf, S., Anizi, H. A., Dael, R., AlMazroa, M., Asiri, A., Memish, Z. A., Ghazal, S. S., Alfaraj, S. H., Harthy, A. A., Sulaiman, M. A., Mady, A., Ahmad, A., Ghaleb, A. A., Muhammed, R., Samirrai, S. A., Awad, S., Cabal, R. C., Onazi, B. A., Aljuhani, M., Vince, M., Enani, M. A., Alqurashi, A., Alenezi, F., Alkhani, N., Thaqafi, A., Oraabi, O. A., Rifai, J., Elsamadisi, P., Medhat, S. H., Basher, S. A., Abduldhaher, M., Bajhamoum, W., Alahsa, S. S., Bashir, S., Al-Dossary, I., Al-Muhainy Dammam, B., Khobar, S. S. A., Alshahrani, M. S., Al Jabri, A., Farid, M., Alaidarous, A., Alseraihi, W., Shahada, H., and Taif, J. S. (2018) Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): Study protocol for a randomized controlled trial. Trials 19, n/a,  DOI: 10.1186/s13063-017-2427-0
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    Zeldin, R. K. and Petruschke, R. A. (2003) Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J. Antimicrob. Chemother. 53 (1), 4– 9,  DOI: 10.1093/jac/dkh029
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    Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L. W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., and Yang, H. (2020) Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature  DOI: 10.1038/s41586-020-2223-y
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    Anandakrishnan, R., Aguilar, B., and Onufriev, A. V. (2012) H++ 3.0: Automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Res. 40 (W1), W537– W541,  DOI: 10.1093/nar/gks375
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    H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations
    Anandakrishnan, Ramu; Aguilar, Boris; Onufriev, Alexey V.
    Nucleic Acids Research (2012), 40 (W1), W537-W541CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The accuracy of atomistic biomol. modeling and simulation studies depend on the accuracy of the input structures. Prepg. these structures for an atomistic modeling task, such as mol. dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topol. files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the prepn. of biomol. structures for mol. modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addn. to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified no. of common ions for explicit solvent MD.
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    Otto, H. H. and Schirmeister, T. (1997) Cysteine proteases and their inhibitors. Chem. Rev. 97 (1), 133– 171,  DOI: 10.1021/cr950025u
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    Otto, Hans-Hartwig; Schirmeister, Tanja
    Chemical Reviews (Washington, D. C.) (1997), 97 (1), 133-171CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review with 599 refs. Some typical examples of cysteine proteases from different sources are characterized in terms of property, structure and specificity. Possible functions of human and mammalian cysteine proteases, lysosomal cathepsins and cytoplasmic calpains are discussed, as well as their role in pathol. processes. In addn. to the endogenous inhibitors, the cystatins and calpastatins, the currently available synthetic inhibitors are also described together with their structures, reaction mechanisms, activities and selectivities. Potential medical applications of cysteine protease inhibitors are discussed. Particular emphasis is given to comparison of cysteine proteases with serine proteases, due to their similar proteolytic mechanisms.
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    ZINC 15 - Ligand Discovery for Everyone
    Sterling, Teague; Irwin, John J.
    Journal of Chemical Information and Modeling (2015), 55 (11), 2324-2337CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Many questions about the biol. activity and availability of small mols. remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biol., we have developed a suite of ligand annotation, purchasability, target, and biol. assocn. tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compds. - effectively all org. mols. that are for sale - a quarter of which are available for immediate delivery. ZINC connects purchasable compds. to high-value ones such as metabolites, drugs, natural products, and annotated compds. from the literature. Compds. may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new anal. tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots - all mols. are available in biol. relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.
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  25. 25
    Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F., Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A., Jr., Peralta, J. E., Ogliaro, F., Bearpark, M. J., Heyd, J., Brothers, E. N., Kudin, K. N., Staroverov, V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A. P., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, N. J., Klene, M., Knox, J. E., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, Ö., Foresman, J. B., Ortiz, J. V., Cioslowski, J., and Fox, D. J. (2009) Gaussian 09, Gaussian, Inc., Wallingford, CT.
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    Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., and Simmerling, C. (2015) ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J. Chem. Theory Comput. 11 (8), 3696– 3713,  DOI: 10.1021/acs.jctc.5b00255
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    26
    ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB
    Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik; Wickstrom, Lauren; Hauser, Kevin E.; Simmerling, Carlos
    Journal of Chemical Theory and Computation (2015), 11 (8), 3696-3713CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    Mol. mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Av. errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a phys. motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reprodn. of NMR χ1 scalar coupling measurements for proteins in soln. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
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    Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004) Development and testing of a general Amber force field. J. Comput. Chem. 25 (9), 1157– 1174,  DOI: 10.1002/jcc.20035
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    Development and testing of a general Amber force field
    Wang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.
    Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
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    Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., and Klein, M. L. (1983) Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79 (2), 926– 935,  DOI: 10.1063/1.445869
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    Comparison of simple potential functions for simulating liquid water
    Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
    Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
    Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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    Meeprasert, A., Hannongbua, S., and Rungrotmongkol, T. (2014) Key binding and susceptibility of NS3/4A serine protease inhibitors against hepatitis C virus. J. Chem. Inf. Model. 54 (4), 1208– 1217,  DOI: 10.1021/ci400605a
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    29
    Key Binding and Susceptibility of NS3/4A Serine Protease Inhibitors against Hepatitis C Virus
    Meeprasert, Arthitaya; Hannongbua, Supot; Rungrotmongkol, Thanyada
    Journal of Chemical Information and Modeling (2014), 54 (4), 1208-1217CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Hepatitis C virus (HCV) causes an infectious disease that manifests itself as liver inflammation, cirrhosis, and can lead to the development of liver cancer. Its NS3/4A serine protease is a potent target for drug design and development since it is responsible for cleavage of the scissile peptide bonds in the polyprotein important for the HCV life cycle. Herein, the ligand-target interactions and the binding free energy of the four current NS3/4A inhibitors (boceprevir, telaprevir, danoprevir, and BI201335) were investigated by all-atom mol. dynamics simulations with three different initial at. velocities. The per-residue free energy decompn. suggests that the key residues involved in inhibitor binding were residues 41-43, 57, 81, 136-139, 155-159, and 168 in the NS3 domain. The van der Waals interactions yielded the main driving force for inhibitor binding at the protease active site for the cleavage reaction. In addn., the highest no. of hydrogen bonds was formed at the reactive P1 site of the four studied inhibitors. Although the hydrogen bond patterns of these inhibitors were different, their P3 site was most likely to be recognized by the A157 backbone. Both mol. mechanic (MM)/Poisson-Boltzmann surface area and MM/generalized Born surface area approaches predicted the relative binding affinities of the four inhibitors in a somewhat similar trend to their exptl. derived biol. activities.
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    Mahalapbutr, P., Wonganan, P., Chavasiri, W., and Rungrotmongkol, T. (2019) Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations. Cancers 11 (4), 437,  DOI: 10.3390/cancers11040437
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    Butoxy mansonone G inhibits STAT3 and Akt signaling pathways in non-small cell lung cancers: combined experimental and theoretical investigations
    Mahalapbutr, Panupong; Wonganan, Piyanuch; Chavasiri, Warinthorn; Rungrotmongkol, Thanyada
    Cancers (2019), 11 (4), 437CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
    Epidermal growth factor receptor (EGFR) is the key mol. target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-contg. compd., and its semi-synthetic ether derivs. were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC50 of 8.54 μM) and H1975 (IC50 of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC50 of 21.16 μM).Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns mol. dynamics simulations and the mol. mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calcns. suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component anal., the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, esp. the residues in the active site, stabilizing MG3 mainly through van der Waals interactions.
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    Nutho, B. and Rungrotmongkol, T. (2019) Binding recognition of substrates in NS2B/NS3 serine protease of Zika virus revealed by molecular dynamics simulations. J. Mol. Graphics Modell. 92, 227– 235,  DOI: 10.1016/j.jmgm.2019.08.001
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    Binding recognition of substrates in NS2B/NS3 serine protease of Zika virus revealed by molecular dynamics simulations
    Nutho, Bodee; Rungrotmongkol, Thanyada
    Journal of Molecular Graphics & Modelling (2019), 92 (), 227-235CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
    Zika virus (ZIKV) has become a global public health concern. The recent epidemiol. data has revealed a possible assocn. of ZIKV infection with more serious complications, particularly for Guillain-Barre´ syndrome in adults and microcephaly in newborn children. Till now, there is no vaccine or effective drug com. available to combat with ZIKV infection. An attractive drug target for the ZIKV treatment is the NS2B/NS3 serine protease, which is essential for viral polyprotein processing. Herein, classical mol. dynamics (MD) simulations were performed on the ZIKV NS2B/NS3 serine protease in complex with four peptide substrates to investigate the binding recognition and protein-substrate interactions. The obtained results indicate that the P1 and P2 positions of the substrate play a significant role in binding with the protease enzyme, while the P3 and P4 positions show a minor contribution in binding interaction. Moreover, the binding free energy calcn. based on the MM/PBSA method suggests that among the four similar peptide substrates, the peptide Ac-D-RKOR-ACC displays the strongest binding affinity towards the ZIKV protease due to the high energy contribution at the S2 subsite particularly for the NS3 residue D75 with the P2(O) residue of this substrate, which is in line with the exptl. data. Thus, the information derived from MD simulations presented here would be useful for the design of potent protease inhibitors.
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    Kammarabutr, J., Mahalapbutr, P., Nutho, B., Kungwan, N., and Rungrotmongkol, T. (2019) Low susceptibility of asunaprevir towards R155K and D168A point mutations in HCV NS3/4A protease: A molecular dynamics simulation. J. Mol. Graphics Modell. 89, 122– 130,  DOI: 10.1016/j.jmgm.2019.03.006
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    Low susceptibility of asunaprevir towards R155K and D168A point mutations in HCV NS3/4A protease: A molecular dynamics simulation
    Kammarabutr, Jirayu; Mahalapbutr, Panupong; Nutho, Bodee; Kungwan, Nawee; Rungrotmongkol, Thanyada
    Journal of Molecular Graphics & Modelling (2019), 89 (), 122-130CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
    Hepatitis C has become an important health problem that requires expensive treatment and leads to liver tumorigenesis. Hepatitis C virus (HCV), which is the main cause of hepatitis C, has a high mutation rate due to the lack of proofreading activity of the RNA polymerase enzyme. The NS3/4A serine protease is an important target for anti-HCV drug discovery and development because of its crucial role in the cleavage of the polypeptides involved in viral replication. In the present study, all-atom mol. dynamics simulation was performed to elucidate the effect of the single point mutations R155K and D168A in the HCV genotype 1 NS3/4A protease on the structural dynamics, mol. interactions and susceptibility of asunaprevir (ASV), a second-generation NS3/4A protease inhibitor. Principal component anal. indicated that these two mutations converted the direction of motion of residues 123, 155 and 168 in the binding pocket to significantly point outwards from ASV, resulting in a loss of the hydrogen bond network of residues R123···R155···D168. The free energy calcns. based on different semiempirical QM/MM-GBSA methods revealed that the binding affinity of ASV with the two mutant forms of the NS3/4A protease was significantly decreased in the order of wild-type ≤ R155K ≤ D168A. This work provided useful structural information regarding the atomistic understanding of acquired drug resistance against ASV caused by the R155K and D168A mutations.
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    Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems
    Darden, Tom; York, Darrin; Pedersen, Lee
    Journal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.
    An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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    Ryckaert, Jean Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.
    Journal of Computational Physics (1977), 23 (3), 327-41CODEN: JCTPAH; ISSN:0021-9991.
    A numerical algorithm integrating the 3N Cartesian equation of motion of a system of N points subject to holonomic constraints is applied to mol. dynamics simulation of a liq. of 64 butane mols.
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    Uberuaga, B. P., Anghel, M., and Voter, A. F. (2004) Synchronization of trajectories in canonical molecular-dynamics simulations: Observation, explanation, and exploitation. J. Chem. Phys. 120 (14), 6363– 6374,  DOI: 10.1063/1.1667473
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    Synchronization of trajectories in canonical molecular-dynamics simulations: observation, explanation, and exploitation
    Uberuaga, Blas P.; Anghel, Marian; Voter, Arthur F.
    Journal of Chemical Physics (2004), 120 (14), 6363-6374CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    For two methods commonly used to achieve canonical-ensemble sampling in a mol.-dynamics simulation, the Langevin thermostat and the Andersen [H. C. Andersen, J. Chem. Phys. 72, 2384 (1980)] thermostat, we observe, as have others, synchronization of initially independent trajectories in the same potential basin when the same random no. sequence is employed. For the first time, we derive the time dependence of this synchronization for a harmonic well and show that the rate of synchronization is proportional to the thermostat coupling strength at weak coupling and inversely proportional at strong coupling with a peak in between. Explanations for the synchronization and the coupling dependence are given for both thermostats. Observation of the effect for a realistic 97-atom system indicates that this phenomenon is quite general. We discuss some of the implications of this effect and propose that it can be exploited to develop new simulation techniques. We give three examples: efficient thermalization (a concept which was also noted by Fahy and Hamann [S. Fahy and D. R. Hamann, Phys. Rev. Lett. 69, 761 (1992)]), time-parallelization of a trajectory in an infrequent-event system, and detecting transitions in an infrequent-event system.
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    Berendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.
    Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.
    In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
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    Roe, D. R. and Cheatham, T. E. (2013) PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9 (7), 3084– 3095,  DOI: 10.1021/ct400341p
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    PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
    Roe, Daniel R.; Cheatham, Thomas E.
    Journal of Chemical Theory and Computation (2013), 9 (7), 3084-3095CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the anal. and processing of time series of three-dimensional at. positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange mol. dynamics), image with periodic boundary conditions, create av. structures, strip subsets of the system, and perform calcns. such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
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    Miller, B. R., III, McGee, T. D., Swails, J. M., Homeyer, N., Gohlke, H., and Roitberg, A. E. (2012) MMPBSA.py: An efficient program for end-state free energy calculations. J. Chem. Theory Comput. 8 (9), 3314– 3321,  DOI: 10.1021/ct300418h
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    MMPBSA.py: An Efficient Program for End-State Free Energy Calculations
    Miller, Bill R., III; McGee, T. Dwight, Jr.; Swails, Jason M.; Homeyer, Nadine; Gohlke, Holger; Roitberg, Adrian E.
    Journal of Chemical Theory and Computation (2012), 8 (9), 3314-3321CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    MM-PBSA is a post-processing end-state method to calc. free energies of mols. in soln. MMPBSA.py is a program written in Python for streamlining end-state free energy calcns. using ensembles derived from mol. dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Ref. Interaction Site Model. Vibrational frequencies may be calcd. using normal mode or quasi-harmonic anal. to approx. the solute entropy. Specific interactions can also be dissected using free energy decompn. or alanine scanning. A parallel implementation significantly speeds up the calcn. by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calcns. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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    Feyereisen, M., Fitzgerald, G., and Komornicki, A. (1993) Use of approximate integrals in ab initio theory. An application in MP2 energy calculations. Chem. Phys. Lett. 208 (5–6), 359– 363,  DOI: 10.1016/0009-2614(93)87156-W
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    Use of approximate integrals in ab initio theory. An application in MP2 energy calculations
    Feyereisen, Martin; Fitzgerald, George; Komornicki, Andrew
    Chemical Physics Letters (1993), 208 (5-6), 359-63CODEN: CHPLBC; ISSN:0009-2614.
    Authors use the resoln. of the identity (RI) as a convenient way to replace the use of four-index two-electron integrals with linear combinations of three-index integrals. The method is broadly applicable to a wide range of problems in quantum chem. Authors demonstrate the effectiveness of RI for the calcn. of MP2 energies. For the water dimer, agreement within 0.1 kcal/mol is obtained with respect to exact MP2 calcns. The RI-MP2 energies require only about 10% of the time required by conventional MP2.
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    Kitaura, K., Sugiki, S. I., Nakano, T., Komeiji, Y., and Uebayasi, M. (2001) Fragment molecular orbital method: Analytical energy gradients. Chem. Phys. Lett. 336 (1–2), 163– 170,  DOI: 10.1016/S0009-2614(01)00099-9
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    Fragment molecular orbital method: analytical energy gradients
    Kitaura, K.; Sugiki, S.-I.; Nakano, T.; Komeiji, Y.; Uebayasi, M.
    Chemical Physics Letters (2001), 336 (1,2), 163-170CODEN: CHPLBC; ISSN:0009-2614. (Elsevier Science B.V.)
    The fragment MO (FMO) method, which aimed to calc. large mols. such as proteins, was proposed in a previous work. The method divides a mol. into small fragments and performs MO calcns. on the fragments and the fragment pairs to obtain the total mol. energy. The method with the anal. energy gradient at the HF level of theory has been incorporated into the Gaussian 94 (G94) package. Geometry optimization calcns. using the energy gradients were successfully performed on a model peptide, methyl-capped glycine trimer.
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    Pair interaction energy decomposition analysis
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    Journal of Computational Chemistry (2007), 28 (1), 222-237CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    The energy decompn. anal. (EDA) by Kitaura and Morokuma was redeveloped in the framework of the fragment MO method (FMO). The proposed pair interaction energy decompn. anal. (PIEDA) can treat large mol. clusters and the systems in which fragments are connected by covalent bonds, such as proteins. The interaction energy in PIEDA is divided into the same contributions as in EDA: the electrostatic, exchange-repulsion, and charge transfer energies, to which the correlation (dispersion) term was added. The careful comparison to the ab initio EDA interaction energies for water clusters with 2-16 mols. revealed that PIEDA has the error of at most 1.2 kcal/mol (or about 1%). The anal. was applied to (H2O)1024, the α helix, β turn, and β strand of polyalanine (ALA)10, as well as to the synthetic protein (PDB code 1L2Y) with 20 residues. The comparative aspects of the polypeptide isomer stability are discussed in detail.
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    Hengphasatporn, K., Garon, A., Wolschann, P., Langer, T., Yasuteru, S., Huynh, T. N. T., Chavasiri, W., Saelee, T., Boonyasuppayakorn, S., and Rungrotmongkol, T. (2020) Multiple virtual screening strategies for the discovery of novel compounds active against dengue virus: A hit identification study. Sci. Pharm. 88 (1), 2,  DOI: 10.3390/scipharm88010002
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    Multiple virtual screening strategies for the discovery of novel compounds active against dengue virus: a hit identification study
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    Scientia Pharmaceutica (2020), 88 (1), 2CODEN: SCPHA4; ISSN:2218-0532. (MDPI AG)
    Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the no. of compds. to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from mol. dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compds. presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by detail docking, followed by extensive MD simulations of the complexes. The highest-ranked compd. from this procedure was then synthesized and tested on its inhibitory efficiency by exptl. assays.
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    Mukherjee, P., Shah, F., Desai, P., and Avery, M. (2011) Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. J. Chem. Inf. Model. 51 (6), 1376– 1392,  DOI: 10.1021/ci1004916
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    Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation, and Molecular Dynamics Simulation Studies
    Mukherjee, Prasenjit; Shah, Falgun; Desai, Prashant; Avery, Mitchell
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    SARS-CoV from the coronaviridae family has been identified as the etiol. agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CLpro, a cysteine protease indispensable to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi-nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative anal. of the evaluated compds. and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.
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    Shi, J., Han, N., Lim, L., Lua, S., Sivaraman, J., Wang, L., Mu, Y., and Song, J. (2011) Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain. PLoS Comput. Biol. 7 (2), e1001084– e1001084,  DOI: 10.1371/journal.pcbi.1001084
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    Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain
    Shi, Jiahai; Han, Nanyu; Lim, Liangzhong; Lua, Shixiong; Sivaraman, J.; Wang, Lushan; Mu, Yuguang; Song, Jianxing
    PLoS Computational Biology (2011), 7 (2), e1001084CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)
    Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissocn. const. but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns mol. dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state; in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well sepd. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro.
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    A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters
    Verschueren, Koen H. G.; Pumpor, Ksenia; Anemueller, Stefan; Chen, Shuai; Mesters, Jeroen R.; Hilgenfeld, Rolf
    Chemistry & Biology (Cambridge, MA, United States) (2008), 15 (6), 597-606CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
    Summary: The main proteinase (Mpro) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV Mpro, the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is obsd. to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.
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    Maruyama, K., Sheng, Y., Watanabe, H., Fukuzawa, K., and Tanaka, S. (2018) Application of singular value decomposition to the inter-fragment interaction energy analysis for ligand screening. Comput. Theor. Chem. 1132, 23– 34,  DOI: 10.1016/j.comptc.2018.04.001
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    Application of singular value decomposition to the inter-fragment interaction energy analysis for ligand screening
    Maruyama, Keiya; Sheng, Yinglei; Watanabe, Hirofumi; Fukuzawa, Kaori; Tanaka, Shigenori
    Computational & Theoretical Chemistry (2018), 1132 (), 23-34CODEN: CTCOA5; ISSN:2210-271X. (Elsevier B.V.)
    We evaluated the binding affinity between p38 MAP kinase and various inhibitors through use of the fragment MO (FMO) method at MP2/6-31G* level in comparison to exptl. values of half maximal inhibitory concn. (IC50). Initially, the calcd. results of the FMO-IFIE (inter-fragment interaction energy) sums for 60 complex structures registered in the Protein Data Bank were not well correlated with the IC50 activity data. Therefore, we performed the singular value decompn. (SVD) for the calcd. results of the IFIE matrix (amino acid residues × various ligands) to improve the correlation and det. the cause of the initial poor results. In SVD, the original matrix is divided into multiple vectors that are orthogonal to each other. Through this method, we improved the correlation by removing some particular vectors that involved noise components and impaired the correlation. In addn., the correlation between the IC50 and FMO-IFIE for 22 complex structures of estrogen receptor α (ERα) was also improved in this way. We analyzed the amino acid residues of receptors that were mainly involved in the removed vectors and found an overestimation of the strength of the hydrogen bond between glutamic acid and the ligand.
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    Choi, J., Kim, H. J., Jin, X., Lim, H., Kim, S., Roh, I. S., Kang, H. E., No, K. T., and Sohn, H. J. (2018) Application of the fragment molecular orbital method to discover novel natural products for prion disease. Sci. Rep. 8 (1), 13063,  DOI: 10.1038/s41598-018-31080-7
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    Application of the fragment molecular orbital method to discover novel natural products for prion disease
    Choi Jiwon; Kim Songmi; No Kyoung Tai; Kim Hyo-Jin; Roh In-Soon; Kang Hae-Eun; Sohn Hyun-Joo; Jin Xuemei; Lim Hocheol; No Kyoung Tai
    Scientific reports (2018), 8 (1), 13063 ISSN:.
    Conformational conversion of the normal cellular isoform of the prion protein PrP(C) into an infectious isoform PrP(Sc) causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrP(C) binding site, and effectively reduced PrP(Sc) levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies.
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    Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., and Hilgenfeld, R. (2020) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science eabb3405,  DOI: 10.1126/science.abb3405
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    Shahbaaz, M., Amir, M., Rahman, S., Mustafa Hasan, G., Dohare, R., Bisetty, K., Ahmad, F., Kim, J., and Hassan, M. I. (2018) Structural insights into Rab21 GTPase activation mechanism by molecular dynamics simulations. Mol. Simul. 44 (3), 179– 189,  DOI: 10.1080/08927022.2017.1357813
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    Structural insights into Rab21 GTPase activation mechanism by molecular dynamics simulations
    Shahbaaz, Mohd.; Amir, Mohd.; Rahman, Safikur; Mustafa Hasan, Gulam; Dohare, Ravins; Bisetty, Krishna; Ahmad, Faizan; Kim, Jihoe; Hassan, Md. Imtaiyaz
    Molecular Simulation (2018), 44 (3), 179-189CODEN: MOSIEA; ISSN:0892-7022. (Taylor & Francis Ltd.)
    Rab proteins belong to the family of monomeric GTPases which are involved in the cellular membrane trafficking. Rab21 protein exists in interchangeable GTP- and GDP-bound states. Rabs switch between two active and inactive conformations like other GTPases. The inactive form of Rab is bound to GDP while its active form is bounded with the GTP. Interexchange between active and inactive form is mediated by the GDP/GTP exchange factor (GEF) which catalyzes the conversion from GDP-bound to GTP-bound form, thereby activating the Rab. While the GTP hydrolysis of Rabs is regulated by a GTPase-activating protein (GAP) which causes Rab inactivation. Here, we report the structural flexibility of the Rab21-GTP and Rab21-GDP complexes by docking and mol. dynamics (MD) simulations. Structural anal. of exchange mechanisms of the co-factors complexed with Rab21 reveals that Cys29, Thr33, His48, Gln78 and Lys133 are essentially important in the activation of proteins. Furthermore, a significant change in the orientation of the interacting co-factors, with slight variation in the free energy of binding was obsd. Complexation of GEF with Rab21-GTP and Rab21-GDP reveal a flipping of the switchable residues. Finally, 50 ns MD simulations confirm that the GTP-bound Rab21 complex is thermodynamically more favored than the corresponding GDP-bound complex. This study provides a detailed understanding of the structural elements involved in the conformational changes of Rab21.
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    Mahalapbutr, P., Darai, N., Panman, W., Opasmahakul, A., Kungwan, N., Hannongbua, S., and Rungrotmongkol, T. (2019) Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition. Sci. Rep. 9 (1), 10205,  DOI: 10.1038/s41598-019-46668-w
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    51
    Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition
    Mahalapbutr, Panupong; Darai, Nitchakan; Panman, Wanwisa; Opasmahakul, Aunchan; Kungwan, Nawee; Hannongbua, Supot; Rungrotmongkol, Thanyada
    Scientific Reports (2019), 9 (1), 10205CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-mol.-wt. sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcs. (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calcd. free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower no. of accessible water mols. in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Addnl., the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting mol.
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    Cao, K., Li, N., Wang, H., Cao, X., He, J., Zhang, B., He, Q.-Y., Zhang, G., and Sun, X. (2018) Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc. J. Biol. Chem. 293 (16), 6075– 6089,  DOI: 10.1074/jbc.M117.818997
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    Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc
    Cao, Kun; Li, Nan; Wang, Hongcui; Cao, Xin; He, Jiaojiao; Zhang, Bing; He, Qing-Yu; Zhang, Gong; Sun, Xuesong
    Journal of Biological Chemistry (2018), 293 (16), 6075-6089CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Zinc is an essential metal in bacteria. One important bacterial zinc transporter is AdcA, and most bacteria possess AdcA homologs that are single-domain small proteins due to better efficiency of protein biogenesis. However, a double-domain AdcA with 2 zinc-binding sites is significantly overrepresented in Streptococcus species, many of which are major human pathogens. Here, using mol. dynamics simulations and exptl. validations of AdcA from S. pyogenes, we found that the 2 AdcA domains sequentially stabilized the structure upon zinc binding, indicating an organization required for both increased zinc affinity and transfer speed. This structural organization appeared to endow Streptococcus species with distinct advantages in zinc-depleted environments, which would not be achieved by each single AdcA domain alone. This enhanced zinc transport mechanism sheds light on the significance of the evolution of AdcA domain fusion, provides new insights into double-domain transporter proteins with 2 binding sites for the same ion, and indicates a potential target of antimicrobial drugs against pathogenic Streptococcus species.
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    Duan, L., Feng, G., Wang, X., Wang, L., and Zhang, Q. (2017) Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method. Phys. Chem. Chem. Phys. 19 (15), 10140– 10152,  DOI: 10.1039/C7CP00841D
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    Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method
    Duan, Lili; Feng, Guoqiang; Wang, Xianwei; Wang, Lizhi; Zhang, Qinggang
    Physical Chemistry Chemical Physics (2017), 19 (15), 10140-10152CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    A new highly efficient interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field is employed to investigate the interaction mechanism of CDK2-ligand binding and the effect of the bridging water. Our result shows that the computed binding free energies for five CDK2-ligand complexes using the IE method have a significantly linear correlation with the exptl. measured values with a correlation coeff. of 0.98 in consideration of the bridging water under the PPC force field. And the correlation coeff. is found to be slightly weaker with a value of 0.95 using the traditional normal mode (Nmode) method for calcn. of entropy change. Importantly, the rank of the predicted binding free energies is significantly consistent with the exptl. rank based on the IE method calcd. entropy change using the PPC force field. However, without including the bridging water under PPC simulation, the correlation coeff. is below 0.83. For comparison, the result obtained from the simulation using the nonpolarized AMBER force field gives a much weaker correlation with the correlation coeffs. of 0.44 and 0.45 using the Nmode method and IE method, due to the lack of electrostatic polarization. Furthermore, hydrogen bond anal. indicates that the bridging water makes a significant contribution to mediating the hydrogen bond network of protein-ligand binding and stabilizing the complex structure. The current study demonstrates that the new IE method is superior to the std. Nmode method in computing the binding free energy. And our results also emphasize the importance of electronic polarization and bridging water in MD simulations and free energy calcns.
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  • Abstract

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    Figure 1

    Figure 1. (A) Three-dimensional structure of the peptidelike inhibitor binding to the active site of the SARS-CoV-2 3CLpro homodimer (PDB entry 6LU7) in one asymmetric unit (A, yellow; B, cyan). Protomers are shown as ribbons, and the inhibitor is shown as an orange ball and stick model. Chemical structures of (B) lopinavir and (C) ritonavir, where the atomic labels are also given.

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    Figure 2

    Figure 2. All-atom RMSD, # H-bonds, and # atom contacts of lopinavir (left) and ritonavir (right) in complex with SARS-CoV-2 3CLpro plotted along the 100 ns MD simulation.

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    Figure 3

    Figure 3. ΔGbindresidue values of lopinavir (top) and ritonavir (bottom) in complex with SARS-CoV-2 3CLpro. The contributing residues involved in ligand binding are colored according to their ΔGbindresidue values, where the highest to lowest free energies are shaded from gray to blue, respectively.

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    Figure 4

    Figure 4. Superimposed structures over the 20 snapshots of (A) lopinavir and (B) ritonavir in complex with SARS-CoV-2 3CLpro derived from the last 20 ns of MD simulations.

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    Figure 5

    Figure 5. Electrostatic (ΔEele + ΔGpolar, black line) and vdW (ΔEvdW + ΔGnonpolar, red line) energy contributions from each residue of SARS-CoV-2 3CLpro to the binding of lopinavir (top) and ritonavir (bottom).

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    Figure 6

    Figure 6. Pair interaction energy decomposition analysis (PIEDA) of lopinavir (top) and ritonavir (bottom) interacting with individual residues in the binding pocket of SARS-CoV-2 3CLpro based on FMO-MP2/PCM/6-31G* calculation.

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    Figure 7

    Figure 7. Rational drug design of the SARS-CoV-2 3CLpro inhibitors. Note that the green dashed line indicates H-bond formation.

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    Figure 8

    Figure 8. Percentage of H-bond occupation of SARS-CoV-2 3CLpro that contributed to the binding of lopinavir (top) and ritonavir (bottom).

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    Figure 9

    Figure 9. Binding patterns of (A) lopinavir and (B) ritonavir in complex with SARS-CoV-2 3CLpro demonstrated from the last MD snapshot. Black dashed lines represent H-bonds.

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    Figure 10

    Figure 10. (A) SARS-CoV-2 3CLpro homodimer, in which chain A with a drug bound and chain B without a drug bound are shown in shades of yellow and blue, respectively. Note that the amino acid residues within 4 Å (stick model) of the ligand (ball and stick representation) were used for SASA calculations. (B) SASA plots along the simulation time of the two studied systems. (C) Average SASAs of lopinavir and ritonavir systems.

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    Figure 11

    Figure 11. Radial distribution functions, g(r), of the water oxygen atom and integration numbers, n(r), up to the first minimum around the heteroatoms of (A) lopinavir and (B) ritonavir (see Figure 1 for definitions) in complex with SARS-CoV-2 3CLpro. H-Bond water networks of the drug, bridging water, and SARS-CoV-2 3CLpro residue are shown as black dashed lines.

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  • References

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      Lu, Roujian; Zhao, Xiang; Li, Juan; Niu, Peihua; Yang, Bo; Wu, Honglong; Wang, Wenling; Song, Hao; Huang, Baoying; Zhu, Na; Bi, Yuhai; Ma, Xuejun; Zhan, Faxian; Wang, Liang; Hu, Tao; Zhou, Hong; Hu, Zhenhong; Zhou, Weimin; Zhao, Li; Chen, Jing; Meng, Yao; Wang, Ji; Lin, Yang; Yuan, Jianying; Xie, Zhihao; Ma, Jinmin; Liu, William J.; Wang, Dayan; Xu, Wenbo; Holmes, Edward C.; Gao, George F.; Wu, Guizhen; Chen, Weijun; Shi, Weifeng; Tan, Wenjie
      Lancet (2020), 395 (10224), 565-574CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      In late Dec., 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions detd. by rapid amplification of cDNA ends. Phylogenetic anal. of these 2019-nCoV genomes and those of other coronaviruses was used to det. the evolutionary history of the virus and help infer its likely origin. Homol. modeling was done to explore the likely receptor-binding properties of the virus. The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic anal. revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homol. modeling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic anal. suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural anal. suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University. These data have been deposited in the ChinaNational Microbiol. Data Center (accession no. NMDC10013002 and genome accession nos. NMDC60013002-01 to NMDC60013002-10) and the datafrom BGI have been deposited in the China National GeneBank (accession nos. CNA000733235).
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    4. 4
      Brian, D. A. and Baric, R. S. (2005) Coronavirus genome structure and replication. Curr. Top. Microbiol. Immunol. 287, 1– 30,  DOI: 10.1007/3-540-26765-4_1
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      Coronavirus genome structure and replication
      Brian, D. A.; Baric, R. S.
      Current Topics in Microbiology and Immunology (2005), 287 (Coronavirus Replication and Reverse Genetics), 1-30CODEN: CTMIA3; ISSN:0070-217X. (Springer GmbH)
      A review. In addn. to the SARS coronavirus (treated sep. elsewhere in this vol.), the complete genome sequences of six species in the coronavirus genus of the coronavirus family [avian infectious bronchitis virus-Beaudette strain (IBV-Beaudette), bovine coronavirus-ENT strain (BCoV-ENT), human coronavirus-229E strain (HCoV-229E), murine hepatitis virus-A59 strain (MHV-A59), porcine transmissible gastroenteritis-Purdue 115 strain (TGEV-Purdue 115), and porcine epidemic diarrhea virus-CV777 strain (PEDV-CV777)] have now been reported. Their lengths range from 27,317 nt for HCoV-229E to 31,357 nt for the murine hepatitis virus-A59, establishing the coronavirus genome as the largest known among RNA viruses. The basic organization of the coronavirus genome is shared with other members of the Nidovirus order (the torovirus genus, also in the family Coronaviridae, and members of the family Arteriviridae) in that the nonstructural proteins involved in proteolytic processing, genome replication, and subgenomic mRNA synthesis (transcription) (an estd. 14-16 end products for coronaviruses) are encoded within the 5'-proximal two-thirds of the genome on gene 1 and the (mostly) structural proteins are encoded within the 3'-proximal one-third of the genome (8-9 genes for coronaviruses). Genes for the major structural proteins in all coronaviruses occur in the 5' to 3' order as S, E, M, and N. The precise strategy used by coronaviruses for genome replication is not yet known, but many features have been established. This chapter focuses on some of the known features and presents some current questions regarding genome replication strategy, the cis-acting elements necessary for genome replication [as inferred from defective interfering (DI) RNA mols.], the min. sequence requirements for autonomous replication of an RNA replicon, and the importance of gene order in genome replication.
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      Zhang, X. M., Herbst, W., Kousoulas, K. G., and Storz, J. (1994) Biological and genetic characterization of a hemagglutinating coronavirus isolated from a diarrhoeic child. J. Med. Virol. 44 (2), 152– 161,  DOI: 10.1002/jmv.1890440207
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      Biological and genetic characterization of a hemagglutinating coronavirus isolated from a diarrhoeic child
      Zhang, X.M.; Herbst, W.; Kousoulas, K.G.; Storz, J.
      Journal of Medical Virology (1994), 44 (2), 152-61CODEN: JMVIDB; ISSN:0146-6615.
      The coronavirus strain HECV-4408 was isolated from diarrhea fluid of a 6-yr-old child with acute diarrhea and propagated in human rectal tumor (HRT-18) cells. Electron microscopy revealed coronavirus particles in the diarrhea fluid sample and the infected HRT-18 cell cultures. This virus possessed hemagglutinating and acetylesterase activities and caused cytopathic effects in HRT-18 cells but not in MDBK, GBK and FE cells. One of four S-specific monoclonal antibodies reacted in Western blots with HECV-4408, BCV-L9 and BCV-LY138 but not with HCV-OC43, and two reacted with BCV-L9 but not with HECV-4408, BCV-LY138 and HCV-OC43. One S-specific and two N-specific monoclonal antibodies reacted with all of these strains. CDNA encompassing the 3' 8.5 kb of the viral RNA genome was isolated by reverse transcription followed by polymerase chain reaction amplification had size and restriction endonuclease patterns similar to those of BCV-L9 and BCV-LY138. In contrast, the M gene of HCV-OC43 differed in restriction patterns from HECV-4408 and BCV. A genomic deletion located between the S and M within the nonstructural genes of HCV-OC43 was not detected in HECV-4408. DNA sequence analyses of the S and HE genes revealed more than 99% nucleotide and deduced amino acid homologies between HECV-4408 and the virulent wild-type BCV. Forty-nine nucleotide and 22 amino acid differences were found between the HE genes of HECV-4408 and HCV-OC43, while only 16 nucleotide and 3 amino acid differences occurred between the HE genes of HECV-4408 and BCV-LY138. We thus conclude that the strain HECV-4408 is a hemagglutinating enteric coronavirus that is biol., antigenically and genomically more closely related to the virulent BCV-LY138 than to HCV-OC43.
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      Yang, H., Bartlam, M., and Rao, Z. (2006) Drug design targeting the main protease, the Achilles’ heel of coronaviruses. Curr. Pharm. Des. 12 (35), 4573– 4590,  DOI: 10.2174/138161206779010369
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      Drug design targeting the main protease, the Achilles heel of coronaviruses
      Yang, Haitao; Bartlam, Mark; Rao, Zihe
      Current Pharmaceutical Design (2006), 12 (35), 4573-4590CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Coronaviruses (CoVs), a genus contg. about 26 known species to date, cause highly prevalent diseases and are often severe or fatal in humans and animals. In 2003, a previously unknown coronavirus was identified to be the etiol. agent of a global outbreak of a form of life-threatening pneumonia called severe acute respiratory syndrome (SARS). No efficacious therapy is currently available, and vaccines and drugs are under development to prevent SARS-replication infection in many countries. The CoV main protease (Mpro), which plays a pivotal role in viral gene expression and replication through a highly complex cascade involving the proteolytic processing of replicase polyproteins, is an attractive target for drug design. This review summarizes the recent advances in biol. and structural studies, together with development of inhibitors targeting CoV Mpros. It is expected that inhibitors targeting CoV Mpros could be developed into wide-spectrum antiviral drugs against existing and possible future emerging CoV-assocd. diseases.
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    7. 7
      Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., and Cao, B. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497,  DOI: 10.1016/S0140-6736(20)30183-5
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
      Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin
      Lancet (2020), 395 (10223), 497-506CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiol., clin., lab., and radiol. characteristics and treatment and clin. outcomes of these patients. All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analyzed data on patients with lab.-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiol. and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. By Jan 2, 2020, 41 admitted hospital patients had been identified as having lab.-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum prodn. (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) Of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was assocd. with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiol., duration of human transmission, and clin. spectrum of disease need fulfilment by future studies. Ministry of Science and Technol., Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technol. Commission.
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    8. 8
      Xu, R. H., He, J. F., Evans, M. R., Peng, G. W., Field, H. E., Yu, D. W., Lee, C. K., Luo, H. M., Lin, W. S., Lin, P., Li, L. H., Liang, W. J., Lin, J. Y., and Schnur, A. (2004) Epidemiologic clues to SARS origin in China. Emerging Infect. Dis. 10 (6), 1030– 1037,  DOI: 10.3201/eid1006.030852
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      Epidemiologic clues to SARS origin in China
      Xu Rui-Heng; He Jian-Feng; Evans Meiron R; Peng Guo-Wen; Field Hume E; Yu De-Wen; Lee Chin-Kei; Luo Hui-Min; Lin Wei-Sheng; Lin Peng; Li Ling-Hui; Liang Wen-Jia; Lin Jin-Yan; Schnur Alan
      Emerging infectious diseases (2004), 10 (6), 1030-7 ISSN:1080-6040.
      An epidemic of severe acute respiratory syndrome (SARS) began in Foshan municipality, Guangdong Province, China, in November 2002. We studied SARS case reports through April 30, 2003, including data from case investigations and a case series analysis of index cases. A total of 1,454 clinically confirmed cases (and 55 deaths) occurred; the epidemic peak was in the first week of February 2003. Healthcare workers accounted for 24% of cases. Clinical signs and symptoms differed between children (<18 years) and older persons (> or =65 years). Several observations support the hypothesis of a wild animal origin for SARS. Cases apparently occurred independently in at least five different municipalities; early case-patients were more likely than later patients to report living near a produce market (odds ratio undefined; lower 95% confidence interval 2.39) but not near a farm; and 9 (39%) of 23 early patients, including 6 who lived or worked in Foshan, were food handlers with probable animal contact.
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    9. 9
      de Groot, R. J., Baker, S. C., Baric, R. S., Brown, C. S., Drosten, C., Enjuanes, L., Fouchier, R. A. M., Galiano, M., Gorbalenya, A. E., Memish, Z. A., Perlman, S., Poon, L. L. M., Snijder, E. J., Stephens, G. M., Woo, P. C. Y., Zaki, A. M., Zambon, M., and Ziebuhr, J. (2013) Middle east respiratory syndrome coronavirus (MERS-CoV): Announcement of the coronavirus study group. J. Virol. 87 (14), 7790– 7792,  DOI: 10.1128/JVI.01244-13
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      Middle east respiratory syndrome coronavirus (MERS-CoV): announcement of the coronavirus study group
      de Groot, Raoul J.; Baker, Susan C.; Baric, Ralph S.; Brown, Caroline S.; Drosten, Christian; Enjuanes, Luis; Fouchier, Ron A. M.; Galiano, Monica; Gorbalenya, Alexander E.; Memish, Ziad A.; Perlman, Stanley; Poon, Leo L. M.; Snijder, Eric J.; Stephens, Gwen M.; Woo, Patrick C. Y.; Zaki, Ali M.; Zambon, Maria; Ziebuhr, John
      Journal of Virology (2013), 87 (14), 7790-7792CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      A review. A brief review including epidemiol., description, and consensus name for Middle east respiratory syndrome coronavirus (MERS-CoV).
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    10. 10
      Chan, J. F. W., Yuan, S., Kok, K. H., Chu, K. K. W., Yang, H., Xing, J., Liu, F., Yip, J., Poon, C. C. Y., Tsoi, R. W. S., Lo, H. W., Chan, S. K. F., Poon, K. H., Chan, V. K. M., Ip, W. M., Cai, J. D., Cheng, J. P., Chen, V. C. C., Hui, C. K.-M., To, K. K.-W., and Yuen, K. Y. (2020) A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395, 514,  DOI: 10.1016/S0140-6736(20)30154-9
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      10
      A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster
      Chan, Jasper Fuk-Woo; Yuan, Shuofeng; Kok, Kin-Hang; To, Kelvin Kai-Wang; Chu, Hin; Yang, Jin; Xing, Fanfan; Liu, Jieling; Yip, Cyril Chik-Yan; Poon, Rosana Wing-Shan; Tsoi, Hoi-Wah; Lo, Simon Kam-Fai; Chan, Kwok-Hung; Poon, Vincent Kwok-Man; Chan, Wan-Mui; Ip, Jonathan Daniel; Cai, Jian-Piao; Cheng, Vincent Chi-Chung; Chen, Honglin; Hui, Christopher Kim-Ming; Yuen, Kwok-Yung
      Lancet (2020), 395 (10223), 514-523CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      An ongoing outbreak of pneumonia assocd. with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geog. linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. In this study, we report the epidemiol., clin., lab., radiol., and microbiol. findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an addnl. family member who did not travel to Wuhan. Phylogenetic anal. of genetic sequences from these patients were done. From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Addnl., one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiol. ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiol. ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were neg. for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR pos. for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic anal. of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiratory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travelers in other geog. regions. The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Com. Assocn. South China Microbiol. Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).
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    11. 11
      Su, S., Wong, G., Shi, W., Liu, J., Lai, A. C. K., Zhou, J., Liu, W., Bi, Y., and Gao, G. F. (2016) Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 24 (6), 490– 502,  DOI: 10.1016/j.tim.2016.03.003
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      11
      Epidemiology, genetic recombination, and pathogenesis of coronaviruses
      Su, Shuo; Wong, Gary; Shi, Weifeng; Liu, Jun; Lai, Alexander C. K.; Zhou, Jiyong; Liu, Wenjun; Bi, Yuhai; Gao, George F.
      Trends in Microbiology (2016), 24 (6), 490-502CODEN: TRMIEA; ISSN:0966-842X. (Elsevier Ltd.)
      A review. Human coronaviruses (HCoVs) were first described in the 1960s for patients with the common cold. Since then, more HCoVs have been discovered, including those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), two pathogens that, upon infection, can cause fatal respiratory disease in humans. It was recently discovered that dromedary camels in Saudi Arabia harbor three different HCoV species, including a dominant MERS HCoV lineage that was responsible for the outbreaks in the Middle East and South Korea during 2015. In this review we aim to compare and contrast the different HCoVs with regard to epidemiol. and pathogenesis, in addn. to the virus evolution and recombination events which have, on occasion, resulted in outbreaks amongst humans.
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      De Clercq, E. and Li, G. (2016) Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 29 (3), 695– 747,  DOI: 10.1128/CMR.00102-15
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      Approved Antiviral Drugs over the Past 50 Years
      De Clercq Erik; Li Guangdi
      Clinical microbiology reviews (2016), 29 (3), 695-747 ISSN:.
      Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.
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      Kaplan, S. S. and Hicks, C. B. (2005) Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection. Expert Opin. Pharmacother. 6 (9), 1573– 1585,  DOI: 10.1517/14656566.6.9.1573
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      Lopinavir/ritonavir in the treatment of human immunodeficiency virus infection
      Kaplan, Susan S.; Hicks, Charles B.
      Expert Opinion on Pharmacotherapy (2005), 6 (9), 1573-1585CODEN: EOPHF7; ISSN:1465-6566. (Ashley Publications Ltd.)
      A review. The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clin. value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favorable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clin. trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clin. trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.
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      Chu, C. M., Cheng, V. C. C., Hung, I. F. N., Wong, M. M. L., Chan, K. H., Chan, K. S., Kao, R. Y. T., Poon, L. L. M., Wong, C. L. P., Guan, Y., Peiris, J. S. M., and Yuen, K. Y. (2004) Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 59 (3), 252– 256,  DOI: 10.1136/thorax.2003.012658
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      Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings
      Chu C M; Cheng V C C; Hung I F N; Wong M M L; Chan K H; Chan K S; Kao R Y T; Poon L L M; Wong C L P; Guan Y; Peiris J S M; Yuen K Y
      Thorax (2004), 59 (3), 252-6 ISSN:0040-6376.
      BACKGROUND: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. METHODS: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. RESULTS: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 micro g/ml and 50 micro g/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls-both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. CONCLUSIONS: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.
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    15. 15
      Nukoolkarn, V., Lee, V. S., Malaisree, M., Aruksakulwong, O., and Hannongbua, S. (2008) Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors. J. Theor. Biol. 254 (4), 861– 867,  DOI: 10.1016/j.jtbi.2008.07.030
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      Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CLpro inhibitors
      Nukoolkarn, Veena; Lee, Vannajan Sanghiran; Malaisree, Maturos; Aruksakulwong, Ornjira; Hannongbua, Supot
      Journal of Theoretical Biology (2008), 254 (4), 861-867CODEN: JTBIAP; ISSN:0022-5193. (Elsevier Ltd.)
      Since the emergence of the severe acute respiratory syndrome (SARS) to date, neither an effective antiviral drug nor a vaccine against SARS is available. However, it was found that a mixt. of two HIV-1 proteinase inhibitors, lopinavir and ritonavir, exhibited some signs of effectiveness against the SARS virus. To understand the fine details of the mol. interactions between these proteinase inhibitors and the SARS virus via complexation, mol. dynamics simulations were carried out for the SARS-CoV 3CLpro free enzyme (free SARS) and its complexes with lopinavir (SARS-LPV) and ritonavir (SARS-RTV). The results show that flap closing was clearly obsd. when the inhibitors bind to the active site of SARS-CoV 3CLpro. The binding affinities of LPV and RTV to SARS-CoV 3CLpro do not show any significant difference. In addn., six hydrogen bonds were detected in the SARS-LPV system, while seven hydrogen bonds were found in SARS-RTV complex.
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      Liu, X. and Wang, X.-J. (2020) Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J. Genet. Genomics 47, 119,  DOI: 10.1016/j.jgg.2020.02.001
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      Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines
      Liu Xin; Wang Xiu-Jie
      Journal of genetics and genomics = Yi chuan xue bao (2020), 47 (2), 119-121 ISSN:1673-8527.
      There is no expanded citation for this reference.
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    17. 17
      Zumla, A., Chan, J. F. W., Azhar, E. I., Hui, D. S. C., and Yuen, K. Y. (2016) Coronaviruses-drug discovery and therapeutic options. Nat. Rev. Drug Discovery 15 (5), 327– 347,  DOI: 10.1038/nrd.2015.37
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      Coronaviruses - drug discovery and therapeutic options
      Zumla, Alimuddin; Chan, Jasper F. W.; Azhar, Esam I.; Hui, David S. C.; Yuen, Kwok-Yung
      Nature Reviews Drug Discovery (2016), 15 (5), 327-347CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, resp., have received global attention over the past 12 years owing to their ability to cause community and health-care-assocd. outbreaks of severe infections in human populations. These two viruses pose major challenges to clin. management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiol., virol., clin. features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.
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      Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R., and Hilgenfeld, R. (2003) Coronavirus main proteinase (3CLpro) Structure: Basis for design of anti-SARS drugs. Science 300 (5626), 1763– 1767,  DOI: 10.1126/science.1085658
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      18
      Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs
      Anand, Kanchan; Ziebuhr, John; Wadhwani, Parvesh; Mesters, Jeroen R.; Hilgenfeld, Rolf
      Science (Washington, DC, United States) (2003), 300 (5626), 1763-1767CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (Mpro, also called 3CLpro), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. The authors detd. crystal structures for human coronavirus (strain 229E) Mpro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] Mpro, and the authors constructed a homol. model for SARS coronavirus (SARS-CoV) Mpro. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV Mpro-mediated cleavage of a TGEV Mpro substrate. Mol. modeling suggests that available rhinovirus 3Cpro inhibitors may be modified to make them useful for treating SARS.
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    19. 19
      Arabi, Y. M., Alothman, A., Balkhy, H. H., Al-Dawood, A., AlJohani, S., Al Harbi, S., Kojan, S., Al Jeraisy, M., Deeb, A. M., Assiri, A. M., Al-Hameed, F., AlSaedi, A., Mandourah, Y., Almekhlafi, G. A., Sherbeeni, N. M., Elzein, F. E., Memon, J., Taha, Y., Almotairi, A., Maghrabi, K. A., Qushmaq, I., Al Bshabshe, A., Kharaba, A., Shalhoub, S., Jose, J., Fowler, R. A., Hayden, F. G., Hussein, M. A., Martin, G. S., Schoenfeld, D. A., Walmsley, S. L., Carson, S., Harbi, S. A., Jeraisy, M. A., Muhaidib, M. A., Musharaf, S., Anizi, H. A., Dael, R., AlMazroa, M., Asiri, A., Memish, Z. A., Ghazal, S. S., Alfaraj, S. H., Harthy, A. A., Sulaiman, M. A., Mady, A., Ahmad, A., Ghaleb, A. A., Muhammed, R., Samirrai, S. A., Awad, S., Cabal, R. C., Onazi, B. A., Aljuhani, M., Vince, M., Enani, M. A., Alqurashi, A., Alenezi, F., Alkhani, N., Thaqafi, A., Oraabi, O. A., Rifai, J., Elsamadisi, P., Medhat, S. H., Basher, S. A., Abduldhaher, M., Bajhamoum, W., Alahsa, S. S., Bashir, S., Al-Dossary, I., Al-Muhainy Dammam, B., Khobar, S. S. A., Alshahrani, M. S., Al Jabri, A., Farid, M., Alaidarous, A., Alseraihi, W., Shahada, H., and Taif, J. S. (2018) Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): Study protocol for a randomized controlled trial. Trials 19, n/a,  DOI: 10.1186/s13063-017-2427-0
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      Zeldin, R. K. and Petruschke, R. A. (2003) Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J. Antimicrob. Chemother. 53 (1), 4– 9,  DOI: 10.1093/jac/dkh029
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      Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L. W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., and Yang, H. (2020) Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature  DOI: 10.1038/s41586-020-2223-y
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      Anandakrishnan, R., Aguilar, B., and Onufriev, A. V. (2012) H++ 3.0: Automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Res. 40 (W1), W537– W541,  DOI: 10.1093/nar/gks375
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      H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations
      Anandakrishnan, Ramu; Aguilar, Boris; Onufriev, Alexey V.
      Nucleic Acids Research (2012), 40 (W1), W537-W541CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The accuracy of atomistic biomol. modeling and simulation studies depend on the accuracy of the input structures. Prepg. these structures for an atomistic modeling task, such as mol. dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topol. files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ (http://biophysics.cs.vt.edu/) is a free open-source web server that automates the above key steps in the prepn. of biomol. structures for mol. modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addn. to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified no. of common ions for explicit solvent MD.
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      Otto, H. H. and Schirmeister, T. (1997) Cysteine proteases and their inhibitors. Chem. Rev. 97 (1), 133– 171,  DOI: 10.1021/cr950025u
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      Cysteine Proteases and Their Inhibitors
      Otto, Hans-Hartwig; Schirmeister, Tanja
      Chemical Reviews (Washington, D. C.) (1997), 97 (1), 133-171CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review with 599 refs. Some typical examples of cysteine proteases from different sources are characterized in terms of property, structure and specificity. Possible functions of human and mammalian cysteine proteases, lysosomal cathepsins and cytoplasmic calpains are discussed, as well as their role in pathol. processes. In addn. to the endogenous inhibitors, the cystatins and calpastatins, the currently available synthetic inhibitors are also described together with their structures, reaction mechanisms, activities and selectivities. Potential medical applications of cysteine protease inhibitors are discussed. Particular emphasis is given to comparison of cysteine proteases with serine proteases, due to their similar proteolytic mechanisms.
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      Sterling, T. and Irwin, J. J. (2015) ZINC 15 - Ligand Discovery for Everyone. J. Chem. Inf. Model. 55 (11), 2324– 2337,  DOI: 10.1021/acs.jcim.5b00559
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      ZINC 15 - Ligand Discovery for Everyone
      Sterling, Teague; Irwin, John J.
      Journal of Chemical Information and Modeling (2015), 55 (11), 2324-2337CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Many questions about the biol. activity and availability of small mols. remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biol., we have developed a suite of ligand annotation, purchasability, target, and biol. assocn. tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compds. - effectively all org. mols. that are for sale - a quarter of which are available for immediate delivery. ZINC connects purchasable compds. to high-value ones such as metabolites, drugs, natural products, and annotated compds. from the literature. Compds. may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new anal. tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots - all mols. are available in biol. relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.
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      Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F., Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A., Jr., Peralta, J. E., Ogliaro, F., Bearpark, M. J., Heyd, J., Brothers, E. N., Kudin, K. N., Staroverov, V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A. P., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, N. J., Klene, M., Knox, J. E., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, Ö., Foresman, J. B., Ortiz, J. V., Cioslowski, J., and Fox, D. J. (2009) Gaussian 09, Gaussian, Inc., Wallingford, CT.
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      Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., and Simmerling, C. (2015) ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J. Chem. Theory Comput. 11 (8), 3696– 3713,  DOI: 10.1021/acs.jctc.5b00255
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      26
      ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB
      Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik; Wickstrom, Lauren; Hauser, Kevin E.; Simmerling, Carlos
      Journal of Chemical Theory and Computation (2015), 11 (8), 3696-3713CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      Mol. mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Av. errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a phys. motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reprodn. of NMR χ1 scalar coupling measurements for proteins in soln. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
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      Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004) Development and testing of a general Amber force field. J. Comput. Chem. 25 (9), 1157– 1174,  DOI: 10.1002/jcc.20035
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      Development and testing of a general Amber force field
      Wang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.
      Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.
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      Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., and Klein, M. L. (1983) Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79 (2), 926– 935,  DOI: 10.1063/1.445869
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      Comparison of simple potential functions for simulating liquid water
      Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
      Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
      Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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      Meeprasert, A., Hannongbua, S., and Rungrotmongkol, T. (2014) Key binding and susceptibility of NS3/4A serine protease inhibitors against hepatitis C virus. J. Chem. Inf. Model. 54 (4), 1208– 1217,  DOI: 10.1021/ci400605a
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      29
      Key Binding and Susceptibility of NS3/4A Serine Protease Inhibitors against Hepatitis C Virus
      Meeprasert, Arthitaya; Hannongbua, Supot; Rungrotmongkol, Thanyada
      Journal of Chemical Information and Modeling (2014), 54 (4), 1208-1217CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Hepatitis C virus (HCV) causes an infectious disease that manifests itself as liver inflammation, cirrhosis, and can lead to the development of liver cancer. Its NS3/4A serine protease is a potent target for drug design and development since it is responsible for cleavage of the scissile peptide bonds in the polyprotein important for the HCV life cycle. Herein, the ligand-target interactions and the binding free energy of the four current NS3/4A inhibitors (boceprevir, telaprevir, danoprevir, and BI201335) were investigated by all-atom mol. dynamics simulations with three different initial at. velocities. The per-residue free energy decompn. suggests that the key residues involved in inhibitor binding were residues 41-43, 57, 81, 136-139, 155-159, and 168 in the NS3 domain. The van der Waals interactions yielded the main driving force for inhibitor binding at the protease active site for the cleavage reaction. In addn., the highest no. of hydrogen bonds was formed at the reactive P1 site of the four studied inhibitors. Although the hydrogen bond patterns of these inhibitors were different, their P3 site was most likely to be recognized by the A157 backbone. Both mol. mechanic (MM)/Poisson-Boltzmann surface area and MM/generalized Born surface area approaches predicted the relative binding affinities of the four inhibitors in a somewhat similar trend to their exptl. derived biol. activities.
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    30. 30
      Mahalapbutr, P., Wonganan, P., Chavasiri, W., and Rungrotmongkol, T. (2019) Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations. Cancers 11 (4), 437,  DOI: 10.3390/cancers11040437
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      Butoxy mansonone G inhibits STAT3 and Akt signaling pathways in non-small cell lung cancers: combined experimental and theoretical investigations
      Mahalapbutr, Panupong; Wonganan, Piyanuch; Chavasiri, Warinthorn; Rungrotmongkol, Thanyada
      Cancers (2019), 11 (4), 437CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
      Epidermal growth factor receptor (EGFR) is the key mol. target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-contg. compd., and its semi-synthetic ether derivs. were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC50 of 8.54 μM) and H1975 (IC50 of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC50 of 21.16 μM).Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns mol. dynamics simulations and the mol. mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calcns. suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component anal., the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, esp. the residues in the active site, stabilizing MG3 mainly through van der Waals interactions.
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    31. 31
      Nutho, B. and Rungrotmongkol, T. (2019) Binding recognition of substrates in NS2B/NS3 serine protease of Zika virus revealed by molecular dynamics simulations. J. Mol. Graphics Modell. 92, 227– 235,  DOI: 10.1016/j.jmgm.2019.08.001
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      Binding recognition of substrates in NS2B/NS3 serine protease of Zika virus revealed by molecular dynamics simulations
      Nutho, Bodee; Rungrotmongkol, Thanyada
      Journal of Molecular Graphics & Modelling (2019), 92 (), 227-235CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
      Zika virus (ZIKV) has become a global public health concern. The recent epidemiol. data has revealed a possible assocn. of ZIKV infection with more serious complications, particularly for Guillain-Barre´ syndrome in adults and microcephaly in newborn children. Till now, there is no vaccine or effective drug com. available to combat with ZIKV infection. An attractive drug target for the ZIKV treatment is the NS2B/NS3 serine protease, which is essential for viral polyprotein processing. Herein, classical mol. dynamics (MD) simulations were performed on the ZIKV NS2B/NS3 serine protease in complex with four peptide substrates to investigate the binding recognition and protein-substrate interactions. The obtained results indicate that the P1 and P2 positions of the substrate play a significant role in binding with the protease enzyme, while the P3 and P4 positions show a minor contribution in binding interaction. Moreover, the binding free energy calcn. based on the MM/PBSA method suggests that among the four similar peptide substrates, the peptide Ac-D-RKOR-ACC displays the strongest binding affinity towards the ZIKV protease due to the high energy contribution at the S2 subsite particularly for the NS3 residue D75 with the P2(O) residue of this substrate, which is in line with the exptl. data. Thus, the information derived from MD simulations presented here would be useful for the design of potent protease inhibitors.
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      Kammarabutr, J., Mahalapbutr, P., Nutho, B., Kungwan, N., and Rungrotmongkol, T. (2019) Low susceptibility of asunaprevir towards R155K and D168A point mutations in HCV NS3/4A protease: A molecular dynamics simulation. J. Mol. Graphics Modell. 89, 122– 130,  DOI: 10.1016/j.jmgm.2019.03.006
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      Low susceptibility of asunaprevir towards R155K and D168A point mutations in HCV NS3/4A protease: A molecular dynamics simulation
      Kammarabutr, Jirayu; Mahalapbutr, Panupong; Nutho, Bodee; Kungwan, Nawee; Rungrotmongkol, Thanyada
      Journal of Molecular Graphics & Modelling (2019), 89 (), 122-130CODEN: JMGMFI; ISSN:1093-3263. (Elsevier Ltd.)
      Hepatitis C has become an important health problem that requires expensive treatment and leads to liver tumorigenesis. Hepatitis C virus (HCV), which is the main cause of hepatitis C, has a high mutation rate due to the lack of proofreading activity of the RNA polymerase enzyme. The NS3/4A serine protease is an important target for anti-HCV drug discovery and development because of its crucial role in the cleavage of the polypeptides involved in viral replication. In the present study, all-atom mol. dynamics simulation was performed to elucidate the effect of the single point mutations R155K and D168A in the HCV genotype 1 NS3/4A protease on the structural dynamics, mol. interactions and susceptibility of asunaprevir (ASV), a second-generation NS3/4A protease inhibitor. Principal component anal. indicated that these two mutations converted the direction of motion of residues 123, 155 and 168 in the binding pocket to significantly point outwards from ASV, resulting in a loss of the hydrogen bond network of residues R123···R155···D168. The free energy calcns. based on different semiempirical QM/MM-GBSA methods revealed that the binding affinity of ASV with the two mutant forms of the NS3/4A protease was significantly decreased in the order of wild-type ≤ R155K ≤ D168A. This work provided useful structural information regarding the atomistic understanding of acquired drug resistance against ASV caused by the R155K and D168A mutations.
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      Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems
      Darden, Tom; York, Darrin; Pedersen, Lee
      Journal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.
      An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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      Ryckaert, J. P., Ciccotti, G., and Berendsen, H. J. C. (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23 (3), 327– 341,  DOI: 10.1016/0021-9991(77)90098-5
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      Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes
      Ryckaert, Jean Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.
      Journal of Computational Physics (1977), 23 (3), 327-41CODEN: JCTPAH; ISSN:0021-9991.
      A numerical algorithm integrating the 3N Cartesian equation of motion of a system of N points subject to holonomic constraints is applied to mol. dynamics simulation of a liq. of 64 butane mols.
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      Uberuaga, B. P., Anghel, M., and Voter, A. F. (2004) Synchronization of trajectories in canonical molecular-dynamics simulations: Observation, explanation, and exploitation. J. Chem. Phys. 120 (14), 6363– 6374,  DOI: 10.1063/1.1667473
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      Synchronization of trajectories in canonical molecular-dynamics simulations: observation, explanation, and exploitation
      Uberuaga, Blas P.; Anghel, Marian; Voter, Arthur F.
      Journal of Chemical Physics (2004), 120 (14), 6363-6374CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      For two methods commonly used to achieve canonical-ensemble sampling in a mol.-dynamics simulation, the Langevin thermostat and the Andersen [H. C. Andersen, J. Chem. Phys. 72, 2384 (1980)] thermostat, we observe, as have others, synchronization of initially independent trajectories in the same potential basin when the same random no. sequence is employed. For the first time, we derive the time dependence of this synchronization for a harmonic well and show that the rate of synchronization is proportional to the thermostat coupling strength at weak coupling and inversely proportional at strong coupling with a peak in between. Explanations for the synchronization and the coupling dependence are given for both thermostats. Observation of the effect for a realistic 97-atom system indicates that this phenomenon is quite general. We discuss some of the implications of this effect and propose that it can be exploited to develop new simulation techniques. We give three examples: efficient thermalization (a concept which was also noted by Fahy and Hamann [S. Fahy and D. R. Hamann, Phys. Rev. Lett. 69, 761 (1992)]), time-parallelization of a trajectory in an infrequent-event system, and detecting transitions in an infrequent-event system.
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      Berendsen, H. J. C., Postma, J. P. M., Van Gunsteren, W. F., Dinola, A., and Haak, J. R. (1984) Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81 (8), 3684– 3690,  DOI: 10.1063/1.448118
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      Molecular dynamics with coupling to an external bath
      Berendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.
      Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.
      In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
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      Roe, D. R. and Cheatham, T. E. (2013) PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9 (7), 3084– 3095,  DOI: 10.1021/ct400341p
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      PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
      Roe, Daniel R.; Cheatham, Thomas E.
      Journal of Chemical Theory and Computation (2013), 9 (7), 3084-3095CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the anal. and processing of time series of three-dimensional at. positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange mol. dynamics), image with periodic boundary conditions, create av. structures, strip subsets of the system, and perform calcns. such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
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      Miller, B. R., III, McGee, T. D., Swails, J. M., Homeyer, N., Gohlke, H., and Roitberg, A. E. (2012) MMPBSA.py: An efficient program for end-state free energy calculations. J. Chem. Theory Comput. 8 (9), 3314– 3321,  DOI: 10.1021/ct300418h
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      MMPBSA.py: An Efficient Program for End-State Free Energy Calculations
      Miller, Bill R., III; McGee, T. Dwight, Jr.; Swails, Jason M.; Homeyer, Nadine; Gohlke, Holger; Roitberg, Adrian E.
      Journal of Chemical Theory and Computation (2012), 8 (9), 3314-3321CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      MM-PBSA is a post-processing end-state method to calc. free energies of mols. in soln. MMPBSA.py is a program written in Python for streamlining end-state free energy calcns. using ensembles derived from mol. dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Ref. Interaction Site Model. Vibrational frequencies may be calcd. using normal mode or quasi-harmonic anal. to approx. the solute entropy. Specific interactions can also be dissected using free energy decompn. or alanine scanning. A parallel implementation significantly speeds up the calcn. by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calcns. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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    39. 39
      Feyereisen, M., Fitzgerald, G., and Komornicki, A. (1993) Use of approximate integrals in ab initio theory. An application in MP2 energy calculations. Chem. Phys. Lett. 208 (5–6), 359– 363,  DOI: 10.1016/0009-2614(93)87156-W
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      Use of approximate integrals in ab initio theory. An application in MP2 energy calculations
      Feyereisen, Martin; Fitzgerald, George; Komornicki, Andrew
      Chemical Physics Letters (1993), 208 (5-6), 359-63CODEN: CHPLBC; ISSN:0009-2614.
      Authors use the resoln. of the identity (RI) as a convenient way to replace the use of four-index two-electron integrals with linear combinations of three-index integrals. The method is broadly applicable to a wide range of problems in quantum chem. Authors demonstrate the effectiveness of RI for the calcn. of MP2 energies. For the water dimer, agreement within 0.1 kcal/mol is obtained with respect to exact MP2 calcns. The RI-MP2 energies require only about 10% of the time required by conventional MP2.
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      Kitaura, K., Sugiki, S. I., Nakano, T., Komeiji, Y., and Uebayasi, M. (2001) Fragment molecular orbital method: Analytical energy gradients. Chem. Phys. Lett. 336 (1–2), 163– 170,  DOI: 10.1016/S0009-2614(01)00099-9
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      Fragment molecular orbital method: analytical energy gradients
      Kitaura, K.; Sugiki, S.-I.; Nakano, T.; Komeiji, Y.; Uebayasi, M.
      Chemical Physics Letters (2001), 336 (1,2), 163-170CODEN: CHPLBC; ISSN:0009-2614. (Elsevier Science B.V.)
      The fragment MO (FMO) method, which aimed to calc. large mols. such as proteins, was proposed in a previous work. The method divides a mol. into small fragments and performs MO calcns. on the fragments and the fragment pairs to obtain the total mol. energy. The method with the anal. energy gradient at the HF level of theory has been incorporated into the Gaussian 94 (G94) package. Geometry optimization calcns. using the energy gradients were successfully performed on a model peptide, methyl-capped glycine trimer.
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      Fedorov, D. G. and Kitaura, K. (2007) Pair interaction energy decomposition analysis. J. Comput. Chem. 28 (1), 222– 237,  DOI: 10.1002/jcc.20496
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      Pair interaction energy decomposition analysis
      Fedorov, Dmitri G.; Kitaura, Kazuo
      Journal of Computational Chemistry (2007), 28 (1), 222-237CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      The energy decompn. anal. (EDA) by Kitaura and Morokuma was redeveloped in the framework of the fragment MO method (FMO). The proposed pair interaction energy decompn. anal. (PIEDA) can treat large mol. clusters and the systems in which fragments are connected by covalent bonds, such as proteins. The interaction energy in PIEDA is divided into the same contributions as in EDA: the electrostatic, exchange-repulsion, and charge transfer energies, to which the correlation (dispersion) term was added. The careful comparison to the ab initio EDA interaction energies for water clusters with 2-16 mols. revealed that PIEDA has the error of at most 1.2 kcal/mol (or about 1%). The anal. was applied to (H2O)1024, the α helix, β turn, and β strand of polyalanine (ALA)10, as well as to the synthetic protein (PDB code 1L2Y) with 20 residues. The comparative aspects of the polypeptide isomer stability are discussed in detail.
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      Hengphasatporn, K., Garon, A., Wolschann, P., Langer, T., Yasuteru, S., Huynh, T. N. T., Chavasiri, W., Saelee, T., Boonyasuppayakorn, S., and Rungrotmongkol, T. (2020) Multiple virtual screening strategies for the discovery of novel compounds active against dengue virus: A hit identification study. Sci. Pharm. 88 (1), 2,  DOI: 10.3390/scipharm88010002
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      Multiple virtual screening strategies for the discovery of novel compounds active against dengue virus: a hit identification study
      Hengphasatporn, Kowit; Garon, Arthur; Wolschann, Peter; Langer, Thierry; Yasuteru, Shigeta; Huynh, Thao N. T.; Chavasiri, Warinthorn; Saelee, Thanaphon; Boonyasuppayakorn, Siwaporn; Rungrotmongkol, Thanyada
      Scientia Pharmaceutica (2020), 88 (1), 2CODEN: SCPHA4; ISSN:2218-0532. (MDPI AG)
      Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the no. of compds. to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from mol. dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compds. presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by detail docking, followed by extensive MD simulations of the complexes. The highest-ranked compd. from this procedure was then synthesized and tested on its inhibitory efficiency by exptl. assays.
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      Chen, J., Liang, Z., Wang, W., Yi, C., Zhang, S., and Zhang, Q. (2015) Revealing Origin of Decrease in Potency of Darunavir and Amprenavir against HIV-2 relative to HIV-1 Protease by Molecular Dynamics Simulations. Sci. Rep. 4 (1), 6872,  DOI: 10.1038/srep06872
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      Mukherjee, P., Shah, F., Desai, P., and Avery, M. (2011) Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. J. Chem. Inf. Model. 51 (6), 1376– 1392,  DOI: 10.1021/ci1004916
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      Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation, and Molecular Dynamics Simulation Studies
      Mukherjee, Prasenjit; Shah, Falgun; Desai, Prashant; Avery, Mitchell
      Journal of Chemical Information and Modeling (2011), 51 (6), 1376-1392CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      SARS-CoV from the coronaviridae family has been identified as the etiol. agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CLpro, a cysteine protease indispensable to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi-nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative anal. of the evaluated compds. and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.
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      Shi, J., Han, N., Lim, L., Lua, S., Sivaraman, J., Wang, L., Mu, Y., and Song, J. (2011) Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain. PLoS Comput. Biol. 7 (2), e1001084– e1001084,  DOI: 10.1371/journal.pcbi.1001084
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      45
      Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain
      Shi, Jiahai; Han, Nanyu; Lim, Liangzhong; Lua, Shixiong; Sivaraman, J.; Wang, Lushan; Mu, Yuguang; Song, Jianxing
      PLoS Computational Biology (2011), 7 (2), e1001084CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)
      Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissocn. const. but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns mol. dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state; in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well sepd. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro.
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      Verschueren, K. H. G., Pumpor, K., Anemüller, S., Chen, S., Mesters, J. R., and Hilgenfeld, R. (2008) A structural view of the inactivation of the SARS coronavirus main proteinase by benzotriazole esters. Chem. Biol. 15 (6), 597– 606,  DOI: 10.1016/j.chembiol.2008.04.011
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      46
      A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters
      Verschueren, Koen H. G.; Pumpor, Ksenia; Anemueller, Stefan; Chen, Shuai; Mesters, Jeroen R.; Hilgenfeld, Rolf
      Chemistry & Biology (Cambridge, MA, United States) (2008), 15 (6), 597-606CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
      Summary: The main proteinase (Mpro) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV Mpro, the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is obsd. to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnt1alu74%253D&md5=732c7f2eaa8e5a48aa95bf3a0f9836e7
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      Maruyama, K., Sheng, Y., Watanabe, H., Fukuzawa, K., and Tanaka, S. (2018) Application of singular value decomposition to the inter-fragment interaction energy analysis for ligand screening. Comput. Theor. Chem. 1132, 23– 34,  DOI: 10.1016/j.comptc.2018.04.001
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      Application of singular value decomposition to the inter-fragment interaction energy analysis for ligand screening
      Maruyama, Keiya; Sheng, Yinglei; Watanabe, Hirofumi; Fukuzawa, Kaori; Tanaka, Shigenori
      Computational & Theoretical Chemistry (2018), 1132 (), 23-34CODEN: CTCOA5; ISSN:2210-271X. (Elsevier B.V.)
      We evaluated the binding affinity between p38 MAP kinase and various inhibitors through use of the fragment MO (FMO) method at MP2/6-31G* level in comparison to exptl. values of half maximal inhibitory concn. (IC50). Initially, the calcd. results of the FMO-IFIE (inter-fragment interaction energy) sums for 60 complex structures registered in the Protein Data Bank were not well correlated with the IC50 activity data. Therefore, we performed the singular value decompn. (SVD) for the calcd. results of the IFIE matrix (amino acid residues × various ligands) to improve the correlation and det. the cause of the initial poor results. In SVD, the original matrix is divided into multiple vectors that are orthogonal to each other. Through this method, we improved the correlation by removing some particular vectors that involved noise components and impaired the correlation. In addn., the correlation between the IC50 and FMO-IFIE for 22 complex structures of estrogen receptor α (ERα) was also improved in this way. We analyzed the amino acid residues of receptors that were mainly involved in the removed vectors and found an overestimation of the strength of the hydrogen bond between glutamic acid and the ligand.
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      Choi, J., Kim, H. J., Jin, X., Lim, H., Kim, S., Roh, I. S., Kang, H. E., No, K. T., and Sohn, H. J. (2018) Application of the fragment molecular orbital method to discover novel natural products for prion disease. Sci. Rep. 8 (1), 13063,  DOI: 10.1038/s41598-018-31080-7
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      Application of the fragment molecular orbital method to discover novel natural products for prion disease
      Choi Jiwon; Kim Songmi; No Kyoung Tai; Kim Hyo-Jin; Roh In-Soon; Kang Hae-Eun; Sohn Hyun-Joo; Jin Xuemei; Lim Hocheol; No Kyoung Tai
      Scientific reports (2018), 8 (1), 13063 ISSN:.
      Conformational conversion of the normal cellular isoform of the prion protein PrP(C) into an infectious isoform PrP(Sc) causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrP(C) binding site, and effectively reduced PrP(Sc) levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies.
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      Structural insights into Rab21 GTPase activation mechanism by molecular dynamics simulations
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      Molecular Simulation (2018), 44 (3), 179-189CODEN: MOSIEA; ISSN:0892-7022. (Taylor & Francis Ltd.)
      Rab proteins belong to the family of monomeric GTPases which are involved in the cellular membrane trafficking. Rab21 protein exists in interchangeable GTP- and GDP-bound states. Rabs switch between two active and inactive conformations like other GTPases. The inactive form of Rab is bound to GDP while its active form is bounded with the GTP. Interexchange between active and inactive form is mediated by the GDP/GTP exchange factor (GEF) which catalyzes the conversion from GDP-bound to GTP-bound form, thereby activating the Rab. While the GTP hydrolysis of Rabs is regulated by a GTPase-activating protein (GAP) which causes Rab inactivation. Here, we report the structural flexibility of the Rab21-GTP and Rab21-GDP complexes by docking and mol. dynamics (MD) simulations. Structural anal. of exchange mechanisms of the co-factors complexed with Rab21 reveals that Cys29, Thr33, His48, Gln78 and Lys133 are essentially important in the activation of proteins. Furthermore, a significant change in the orientation of the interacting co-factors, with slight variation in the free energy of binding was obsd. Complexation of GEF with Rab21-GTP and Rab21-GDP reveal a flipping of the switchable residues. Finally, 50 ns MD simulations confirm that the GTP-bound Rab21 complex is thermodynamically more favored than the corresponding GDP-bound complex. This study provides a detailed understanding of the structural elements involved in the conformational changes of Rab21.
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      Mahalapbutr, P., Darai, N., Panman, W., Opasmahakul, A., Kungwan, N., Hannongbua, S., and Rungrotmongkol, T. (2019) Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition. Sci. Rep. 9 (1), 10205,  DOI: 10.1038/s41598-019-46668-w
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      Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition
      Mahalapbutr, Panupong; Darai, Nitchakan; Panman, Wanwisa; Opasmahakul, Aunchan; Kungwan, Nawee; Hannongbua, Supot; Rungrotmongkol, Thanyada
      Scientific Reports (2019), 9 (1), 10205CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-mol.-wt. sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcs. (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calcd. free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower no. of accessible water mols. in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Addnl., the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting mol.
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      Cao, K., Li, N., Wang, H., Cao, X., He, J., Zhang, B., He, Q.-Y., Zhang, G., and Sun, X. (2018) Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc. J. Biol. Chem. 293 (16), 6075– 6089,  DOI: 10.1074/jbc.M117.818997
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      Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc
      Cao, Kun; Li, Nan; Wang, Hongcui; Cao, Xin; He, Jiaojiao; Zhang, Bing; He, Qing-Yu; Zhang, Gong; Sun, Xuesong
      Journal of Biological Chemistry (2018), 293 (16), 6075-6089CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Zinc is an essential metal in bacteria. One important bacterial zinc transporter is AdcA, and most bacteria possess AdcA homologs that are single-domain small proteins due to better efficiency of protein biogenesis. However, a double-domain AdcA with 2 zinc-binding sites is significantly overrepresented in Streptococcus species, many of which are major human pathogens. Here, using mol. dynamics simulations and exptl. validations of AdcA from S. pyogenes, we found that the 2 AdcA domains sequentially stabilized the structure upon zinc binding, indicating an organization required for both increased zinc affinity and transfer speed. This structural organization appeared to endow Streptococcus species with distinct advantages in zinc-depleted environments, which would not be achieved by each single AdcA domain alone. This enhanced zinc transport mechanism sheds light on the significance of the evolution of AdcA domain fusion, provides new insights into double-domain transporter proteins with 2 binding sites for the same ion, and indicates a potential target of antimicrobial drugs against pathogenic Streptococcus species.
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      Duan, L., Feng, G., Wang, X., Wang, L., and Zhang, Q. (2017) Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method. Phys. Chem. Chem. Phys. 19 (15), 10140– 10152,  DOI: 10.1039/C7CP00841D
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      Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method
      Duan, Lili; Feng, Guoqiang; Wang, Xianwei; Wang, Lizhi; Zhang, Qinggang
      Physical Chemistry Chemical Physics (2017), 19 (15), 10140-10152CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      A new highly efficient interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field is employed to investigate the interaction mechanism of CDK2-ligand binding and the effect of the bridging water. Our result shows that the computed binding free energies for five CDK2-ligand complexes using the IE method have a significantly linear correlation with the exptl. measured values with a correlation coeff. of 0.98 in consideration of the bridging water under the PPC force field. And the correlation coeff. is found to be slightly weaker with a value of 0.95 using the traditional normal mode (Nmode) method for calcn. of entropy change. Importantly, the rank of the predicted binding free energies is significantly consistent with the exptl. rank based on the IE method calcd. entropy change using the PPC force field. However, without including the bridging water under PPC simulation, the correlation coeff. is below 0.83. For comparison, the result obtained from the simulation using the nonpolarized AMBER force field gives a much weaker correlation with the correlation coeffs. of 0.44 and 0.45 using the Nmode method and IE method, due to the lack of electrostatic polarization. Furthermore, hydrogen bond anal. indicates that the bridging water makes a significant contribution to mediating the hydrogen bond network of protein-ligand binding and stabilizing the complex structure. The current study demonstrates that the new IE method is superior to the std. Nmode method in computing the binding free energy. And our results also emphasize the importance of electronic polarization and bridging water in MD simulations and free energy calcns.
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