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Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

  • Anjela Manandhar
    Anjela Manandhar
    Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
  • Benjamin E. Blass
    Benjamin E. Blass
    Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
  • Dennis J. Colussi
    Dennis J. Colussi
    Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
  • Imane Almi
    Imane Almi
    Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
    Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, University of Biskra, BP 145, Biskra, 07000, Algeria
    More by Imane Almi
  • Magid Abou-Gharbia
    Magid Abou-Gharbia
    Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
  • Michael L. Klein
    Michael L. Klein
    Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
  • , and 
  • Khaled M. Elokely*
    Khaled M. Elokely
    Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
    *Email: [email protected]
Cite this: J. Chem. Inf. Model. 2021, 61, 2, 1020–1032
Publication Date (Web):February 4, 2021
https://doi.org/10.1021/acs.jcim.0c01457
Copyright © 2021 American Chemical Society

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    Abstract

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    Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested in vitro against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.0c01457.

    • Comparison of loops composed of residues 186–198 in system 1 and system 2 of boceprevir–M3CLpro complex; distance between COMs of Gln189 and boceprevir covalently bound to M3CLpro; timeline of contacts M3CLpro makes with covalently bound boceprevir; comparison of 3D structures of system 1 and system 2 at the end of 1 and 400 ns; analysis of H-bonds of boceprevir with Thr26, Gly143, Ser144, and His164 in system 1; distance between Cα of Thr25 and amine of azabicyclic ring of boceprevir; inhibition assay of HCV protease inhibitors against M3Clpro; RMSDs of M3CLpro backbone and HCV inhibitors; interaction fractions and 2D interaction diagrams of simeprevir, paritaprevir, and asunaprevir with M3CLpro; SMILES of boceprevir, telaprevir, narlaprevir, asunaprevir, simeprevir, and paritaprevir (PDF)

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