Visualized and Quantitative Conformational Analysis of Peptidomimetics

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1. 1

   Conte, L. L.; Chothia, C.; Janin, J. The Atomic Structure of Protein-Protein Recognition Sites. J. Mol. Biol. 1999, 285, 2177– 2198,  DOI: 10.1006/jmbi.1998.2439

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   Guharoy, M.; Chakrabarti, P. Secondary Structure Based Analysis and Classification of Biological Interfaces: Identification of Binding Motifs in Protein-Protein Interactions. Bioinformatics 2007, 23, 1909– 1918,  DOI: 10.1093/bioinformatics/btm274

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   Secondary structure based analysis and classification of biological interfaces: identification of binding motifs in protein-protein interactions

   Guharoy, Mainak; Chakrabarti, Pinak

   Bioinformatics (2007), 23 (15), 1909-1918CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)

   The increasing amt. of data on protein-protein interaction needs to be rationalized for deriving guidelines for the alteration or design of an interface between 2 proteins. The authors present a detailed structural anal. and comparison of homo- vs. heterodimeric protein-protein interfaces. Regular secondary structures (helixes and strands) are the main components of the former, whereas non-regular structures (turns, loops, etc.) frequently mediate interactions in the latter. Interface helixes get longer with increasing interface area, but only in heterocomplexes. On av., the homodimers have longer helical segments and prominent helix-helix pairs. There is a surprising distinction in the relative orientation of interface helixes, with a tendency for aligned packing in homodimers and a clear preference for packing at 90° in heterodimers. Arg and the arom. residues have a higher preference to occur in all secondary structural elements (SSEs) in the interface. Based on the dominant SSE, the interfaces have been grouped into four classes: α, β, αβ and non-regular. Identity between protein and interface classes is the max. for α proteins, but rather mediocre for the other protein classes. The interface classes of the two chains forming a heterodimer are often dissimilar. Eleven binding motifs can capture the prominent architectural features of most of the interfaces.
3. 3

   Sawyer, N.; Watkins, A. M.; Arora, P. S. Protein Domain Mimics as Modulators of Protein–Protein Interactions. Acc. Chem. Res. 2017, 50, 1313– 1322,  DOI: 10.1021/acs.accounts.7b00130

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   Protein Domain Mimics as Modulators of Protein-Protein Interactions

   Sawyer, Nicholas; Watkins, Andrew M.; Arora, Paramjit S.

   Accounts of Chemical Research (2017), 50 (6), 1313-1322CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

   A review. Protein-protein interactions (PPIs) are ubiquitous in biol. systems and often misregulated in disease. As such, specific PPI modulators are desirable to unravel complex PPI pathways and expand the no. of druggable targets available for therapeutic intervention. However, the large size and relative flatness of PPI interfaces make them challenging mol. targets. Here, the authors describe their systematic approach using secondary and tertiary protein domain mimics (PDMs) to specifically modulate PPIs. This strategy focuses on mimicry of regular secondary and tertiary structure elements from one of the PPI partners to inspire rational PDM design. We have compiled three databases (HIPPDB, SIPPDB, and DIPPDB) of secondary and tertiary structures at PPI interfaces to guide the designs and better understand the energetics of PPI secondary and tertiary structures. The efforts have focused on 3 of the most common secondary and tertiary structures: α-helixes, β-strands, and helix dimers (e.g., coiled-coils). To mimic α-helixes, we designed the H-bond surrogate (HBS) as an isosteric PDM and the oligo-oxopiperazine helix mimetic (OHM) as a topog. PDM. The nucleus of the HBS approach is a peptide macrocycle in which the N-terminal i, i+4 main-chain H-bond is replaced with a covalent C-C bond. In mimicking a main-chain H-bond, the HBS approach stabilizes the α-helical conformation while leaving all helical faces available for functionalization to tune binding affinity and specificity. The OHM approach, in contrast, envisions a tetrapeptide to mimic one face of a 2-turn helix. We anticipated that placement of ethylene bridges between adjacent amides constrains the tetrapeptide backbone to mimic the i, i+4, and i+7 side-chains on one face of an α-helix. For β-strands, we developed triazolamers, a topog. PDM where the peptide bonds are replaced by triazoles. The triazoles simultaneously stabilize the extended, zigzag conformation of β-strands and transform an otherwise ideal protease substrate into a stable mol. by replacement of the peptide bonds. We turned to a salt bridge surrogate (SBS) approach as a means for stabilizing very short helix dimers. As with the HBS approach, the SBS strategy replaces a noncovalent interaction with a covalent bond. Specifically, we used a bis-triazole linkage that mimics a salt bridge interaction to drive helix assocn. and folding. Using this approach, we were able to stabilize helix dimers that are less than half of the length required to form a coiled-coil from 2 independent strands. In addn. to demonstrating the stabilization of desired structures, we have also shown that our designed PDMs specifically modulate target PPIs in vitro and in vivo. Examples of PPIs successfully targeted include HIF1α/p300, p53/MDM2, Bcl-xL/Bak, Ras/Sos, and HIV gp41. The PPI databases and designed PDMs created in these studies will aid development of a versatile set of mols. to probe complex PPI functions and, potentially, PPI-based therapeutics.
4. 4

   Milroy, L. G.; Grossmann, T. N.; Sven, H.; Luc, B.; Christian, O. Modulators of Protein- Protein Interactions. Chem. Rev. 2014, 114, 4695– 4748,  DOI: 10.1021/cr400698c

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   Modulators of Protein-Protein Interactions

   Milroy, Lech-Gustav; Grossmann, Tom N.; Hennig, Sven; Brunsveld, Luc; Ottmann, Christian

   Chemical Reviews (Washington, DC, United States) (2014), 114 (9), 4695-4748CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

   A review. Since Hedin's characterization of trypsin and antitrypsin in 1906, arguably the first account of a regulatory protein-protein interaction (PPI), contemporary understanding of proteins and PPIs has been progressively transformed by landmark conceptual and technol. advances in mol. cell biol., biochem. and biophysics, not least, the sequencing of the human genome and the ensuing genomic technologies. Today, proteins can be viewed as the mol. smart phones of the cell, genetically programmed to enact specific cellular functions in response to external stimuli. Individually, proteins perform essential functions such as catalysis and the transport of mols. and ions. However,their effectiveness in the crowded cellular environment is only short-range and insufficient to sustain life without the involvement of other biomols. such as other proteins or metabolites. This review begins with a up-to-date account of the principle biochem. techniques used to identify PPI modulators.
5. 5

   Bullock, B. N.; Jochim, A. L.; Arora, P. S. Assessing Helical Protein Interfaces for Inhibitor Design. J. Am. Chem. Soc. 2011, 133, 14220– 14223,  DOI: 10.1021/ja206074j

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   Assessing Helical Protein Interfaces for Inhibitor Design

   Bullock, Brooke N.; Jochim, Andrea L.; Arora, Paramjit S.

   Journal of the American Chemical Society (2011), 133 (36), 14220-14223CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   Structure-based design of synthetic inhibitors of protein-protein interactions (PPIs) requires adept mol. design and synthesis strategies as well as knowledge of targetable complexes. To address the significant gap between the elegant design of helix mimetics and their sporadic use in biol., the authors analyzed the full set of helical protein interfaces in the Protein Data Bank to obtain a snapshot of how helixes that are crit. for complex formation interact with the partner proteins. The results of this study are expected to guide the systematic design of synthetic inhibitors of PPIs. The authors have exptl. evaluated new classes of protein complexes that emerged from this data set, highlighting the significance of the results described herein.
6. 6

   Pelay-Gimeno, M.; Glas, A.; Koch, O.; Grossmann, T. N. Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes. Angew. Chem., Int. Ed. 2015, 54, 8896– 8927,  DOI: 10.1002/anie.201412070

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   Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes

   Pelay-Gimeno, Marta; Glas, Adrian; Koch, Oliver; Grossmann, Tom N.

   Angewandte Chemie, International Edition (2015), 54 (31), 8896-8927CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A review. Protein-protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding mols. that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A-D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helixes.
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   Watkins, A. M.; Bonneau, R.; Arora, P. S. Side-Chain Conformational Preferences Govern Protein-Protein Interactions. J. Am. Chem. Soc. 2016, 138, 10386– 10389,  DOI: 10.1021/jacs.6b04892

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   Side-Chain Conformational Preferences Govern Protein-Protein Interactions

   Watkins, Andrew M.; Bonneau, Richard; Arora, Paramjit S.

   Journal of the American Chemical Society (2016), 138 (33), 10386-10389CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   Protein secondary structures serve as geometrically constrained scaffolds for the display of key interacting residues at protein interfaces. Given the crit. role of secondary structures in protein folding and the dependence of folding propensities on backbone dihedrals, secondary structure is expected to influence the identity of residues that are important for complex formation. Counter to this expectation, the authors found that a narrow set of residues dominates the binding energy in protein-protein complexes independent of backbone conformation. This finding suggests that the binding epitope may instead be substantially influenced by the side-chain conformations adopted. The authors analyzed side-chain conformational preferences in residues that contributed significantly to binding. This anal. suggested that preferred rotamers contribute directly to specificity in protein complex formation and provided guidelines for peptidomimetic inhibitor design.
8. 8

   Davis, J. M.; Tsou, L. K.; Hamilton, A. D. Synthetic Non-Peptide Mimetics of α-Helices. Chem. Soc. Rev. 2007, 36, 326– 334,  DOI: 10.1039/B608043J

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   Synthetic non-peptide mimetics of α-helices

   Davis, Jessica M.; Tsou, Lun K.; Hamilton, Andrew D.

   Chemical Society Reviews (2007), 36 (2), 326-334CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

   A review. Proteins in nature fold into native conformations in which combinations of peripherally projected aliph., arom. and ionic functionalities direct a wide range of properties. α-Helixes, one of the most common protein secondary structures, serve as important recognition regions on protein surfaces for numerous protein-protein, protein-DNA and protein-RNA interactions. These interactions are characterized by conserved structural features within the α-helical domain. Rational design of structural mimetics of these domains with synthetic small mols. has proven an effective means to modulate such protein functions. In this tutorial review the authors discuss strategies that utilize synthetic small-mol. antagonists to selectively target essential protein-protein interactions involved in certain diseases. The authors also evaluate some of the protein-protein interactions that have been or are potential targets for α-helix mimetics.
9. 9

   Jayatunga, M. K. P.; Thompson, S.; Hamilton, A. D. α-Helix Mimetics: Outwards and Upwards. Bioorg. Med. Chem. Lett. 2014, 24, 717– 724,  DOI: 10.1016/j.bmcl.2013.12.003

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   α-Helix mimetics: Outwards and upwards

   Jayatunga, Madura K. P.; Thompson, Sam; Hamilton, Andrew D.

   Bioorganic & Medicinal Chemistry Letters (2014), 24 (3), 717-724CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

   A review. α-Helixes are common secondary structural elements forming key parts of the large, generally featureless interfacial regions of many therapeutically-relevant protein-protein interactions (PPIs). The rational design of helix mimetics is an appealing small-mol. strategy for the mediation of aberrant PPIs, however the first generation of scaffolds presented a relatively small no. of residues on a single recognition surface. Increasingly, helixes involved in PPIs are found to have more complex binding modes, utilizing two or three recognition surfaces, or binding with extended points of contact. To address these unmet needs the design and synthesis of new generations of multi-sided, extended, and supersecondary structures are underway.
10. 10

    Wilson, A. J. Helix Mimetics: Recent Developments. Prog. Biophys. Mol. Biol. 2015, 119, 33– 40,  DOI: 10.1016/j.pbiomolbio.2015.05.001

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    Helix mimetics: Recent developments

    Wilson, Andrew J.

    Progress in Biophysics & Molecular Biology (2015), 119 (1), 33-40CODEN: PBIMAC; ISSN:0079-6107. (Elsevier Ltd.)

    The development of protein-protein interaction (PPIs) inhibitors represents a challenging goal in chem. biol. and drug discovery. PPIs are problematic targets because they involve large surfaces with less well defined features and recognition motifs that are less amenable to conventional exptl. and computational ligand discovery methodologies. α-Helix mediated PPIs represent a sub group with a clearly defined interface and thus may be more amenable to the development of generic ligand discovery methods. Indeed, this is borne out in numerous studies using peptides covalently constrained into a helical conformation resulting in improvement of myriad biophys. and cellular properties. It is however desirable to have small mol. alternatives: a helix mimetic (proteomimetic) is a generic small mol. scaffold that projects functional groups in a similar spatial orientation so as to mimic the presentation of key amino acid side chains from the helix that mediates the PPI. The first true example of a helix mimetic was described over a decade ago however this approach has not yet been elaborated to the extent that it receives similar levels of attention to constrained peptides. This review explores recent significant developments in the area of small mol. α-helix mimetics and provides a crit. overview of success stories, potential limitations of the approach, and areas for future development.
11. 11

    Yin, H.; Lee, G. I.; Hyung, S. P.; Payne, G. A.; Rodriguez, J. M.; Sebti, S. M.; Hamilton, A. D. Terphenyl-Based Helical Mimetics That Disrupt the P53/HDM2 Interaction. Angew. Chem., Int. Ed. 2005, 44, 2704– 2707,  DOI: 10.1002/anie.200462316

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    Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction

    Yin, Hang; Lee, Gui-in; Park, Hyung Soon; Payne, Gregory A.; Rodriguez, Johanna M.; Sebti, Said M.; Hamilton, Andrew D.

    Angewandte Chemie, International Edition (2005), 44 (18), 2704-2707CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    HDM2 regulates p53 by binding to its transactivation domain and promoting its ubiquitin-dependent degrdn. Crystallog. anal. of the HDM2/p53 complex revealed that three hydrophobic residues (F19, W23, L26) along one face of the p53 helical peptide are essential for binding (see picture). Terphenyl-based antagonists mimic the α-helical region of p53 and disrupt HDM2/p53 complexation.
12. 12

    Kutzki, O.; Park, H. S.; Ernst, J. T.; Orner, B. P.; Yin, H.; Hamilton, A. D. Development of a Potent Bcl-XL Antagonist Based on α-Helix Mimicry. J. Am. Chem. Soc. 2002, 124, 11838– 11839,  DOI: 10.1021/ja026861k

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    Development of a potent Bcl-xL antagonist based on α-helix mimicry

    Kutzki, Olaf; Park, Hyung Soon; Ernst, Justin T.; Orner, Brendan P.; Yin, Hang; Hamilton, Andrew D.

    Journal of the American Chemical Society (2002), 124 (40), 11838-11839CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    The rational design of low-mol. wt. ligands that disrupt protein-protein interactions is still a challenging goal in medicinal chem. Our approach to this problem involves the design of mol. scaffolds that mimic the surface functionality projected along one face of an α-helix. Using a terphenyl scaffold, which in a staggered conformation closely reproduces the projection of functionality on the surface of an α-helix, we designed mimics of the pro-apoptotic α-helical Bak-peptide as inhibitors of the Bak/Bcl-xL interaction. This led to the development of a potent Bcl-xL antagonist (KD = 114 nM), whose binding affinity for Bcl-xL was assessed by a fluorescence polarization assay. To det. the binding site of the developed inhibitor we used docking studies and an HSQC-NMR expt. with 15N-labeled Bcl-xL protein. These studies suggest that the inhibitor is binding in the same hydrophobic cleft as the Bak- and Bad-peptides.
13. 13

    Yin, H.; Lee, G. I.; Sedey, K. A.; Rodriguez, J. M.; Wang, H. G.; Sebti, S. M.; Hamilton, A. D. Terephthalamide Derivatives as Mimetics of Helical Peptides: Disruption of the Bcl-XL/Bak Interaction. J. Am. Chem. Soc. 2005, 127, 5463– 5468,  DOI: 10.1021/ja0446404

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    Terephthalamide Derivatives as Mimetics of Helical Peptides: Disruption of the Bcl-xL/Bak Interaction

    Yin, Hang; Lee, Gui-in; Sedey, Kristine A.; Rodriguez, Johanna M.; Wang, Hong-Gang; Sebti, Said M.; Hamilton, Andrew D.

    Journal of the American Chemical Society (2005), 127 (15), 5463-5468CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    A series of Bcl-xL/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the α-helical region of the Bak peptide. These mols. showed favorable in-vitro activities in disrupting the Bcl-xL/Bak BH3 domain complex (terephthalamides I and II, Ki = 0.78 ± 0.07 and 1.85 ± 0.32 μM, resp.). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivs. to disrupt Bcl-xL/Bak complex formation and the size of variable side chains on these mols. Treatment of human HEK293 cells with the terephthalamide deriv. 26 resulted in disruption of the Bcl-xL/Bax interaction in whole cells with an IC50 of 35.0 μM. Computational docking simulations and NMR expts. suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-xL is the target area for these synthetic inhibitors.
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    Shaginian, A.; Whitby, L. R.; Hong, S.; Hwang, I.; Farooqi, B.; Searcey, M.; Chen, J.; Vogt, P. K.; Boger, D. L. Design, Synthesis, and Evaluation of an a-Helix Mimetic Library Targeting Protein-Protein Interactions. J. Am. Chem. Soc. 2009, 131, 5564– 5572,  DOI: 10.1021/ja810025g

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    Design, Synthesis, and Evaluation of an α-Helix Mimetic Library Targeting Protein-Protein Interactions

    Shaginian, Alex; Whitby, Landon R.; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K.; Boger, Dale L.

    Journal of the American Chemical Society (2009), 131 (15), 5564-5572CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    A library of α-helix mimetics such as I are prepd. and tested for their abilities to inhibit protein-protein binding such as that between the proteins p53 and HDM2/MDM2. Eighty compds. based on an initial arylcarbonylaminoarylcarbonylaminobenzoic acid lead compd. are prepd. and tested for their ability to inhibit the binding of p53 to MDM2; aminoacylamino(alkoxy)benzoylamino acid I is found to inhibit the binding most effectively, with an IC50 value of 8 μM. A library of aminoacylamino(alkoxy)benzoylamino acids based on I are prepd. Base-mediated substitution of 4-nitro-3-fluorobenzoic acid with alcs. on preparative scale yields 3-alkoxy-4-nitrobenzoic acids with amino acid side chains or close analogs at the alkoxy groups; coupling of the alkoxynitrobenzoic acids with amino acid tert-Bu esters mediated by HOAt and EDC yields a library of 400 nitro(alkoxy)benzoyl amino acid tert-Bu esters II [R = 4-ClC6H4CH2O, MeO, PhCH2O, 2-(3-indolyl)ethoxy, Me3CO2CCH2O, H, 4-MeOC6H4CH2CH2, (S)-MeOCH2OCHMeCH2O, Me2CHO, TIPSOCH2CH2O, 4-TIPSOC6H4CH2CH2O, MeSCH2CH2O, 1-(triphenylmethyl)-4-imidazolemethyl, Me2CHCH2O, (R)-EtCHMeO, BocNH(CH2)4O, EtO, H2NCOCH2O, 2-naphthylmethoxy, PhCH2CH2O; R1 = 4-ClC6H4, Me, PhCH2, 2-(3-indolyl)ethyl, Me3CO2CCH2, H, 4-MeOC6H4CH2, (S)-(Me3CO)CHMe, Me2CH, Me3COCH2, 4-Me3COC6H4CH2, MeSCH2CH2, 1-(triphenylmethyl)-4-imidazolemethyl, Me2CHCH2, (R)-EtCHMe, BocNH(CH2)4, Et, H2NCOCH2, 2-naphthylmethyl, PhCH2CH2; R2 = O2N; TIPS = triisopropylsilyl; Boc = tert-butoxycarbonyl] on roughly 100 mg scale in 90-100% yields. Microwave-mediated redn. of II (R2 = O2N) with nanopowd. zinc metal and ammonium chloride for 30-300 s yields II (R2 = H2N) ; reaction of II (R2 = H2N) with mixts. of twenty protected amino acids mediated by HOAt and EDC followed by addn. of a polystyrene-bound sulfonyl chloride to scavenge excess II and acid deprotection using HCl in dioxane yields a library of 400 mixts. of 20 aminoacylaminobenzoylamino acids. The variation of inhibition of the binding of p53 to MDM2 by the library is detd. The library is generated in stored such that it may be preserved and used for further testing as a α-helix peptidomimetic library for lead compd. generation.
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    Burslem, G. M.; Kyle, H. F.; Breeze, A. L.; Edwards, T. A.; Nelson, A.; Warriner, S. L.; Wilson, A. J. Small-Molecule Proteomimetic Inhibitors of the HIF-1α-P300 Protein-Protein Interaction. ChemBioChem 2014, 15, 1083– 1087,  DOI: 10.1002/cbic.201400009

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    Small-Molecule Proteomimetic Inhibitors of the HIF-1α-p300 Protein-Protein Interaction

    Burslem, George M.; Kyle, Hannah F.; Breeze, Alexander L.; Edwards, Thomas A.; Nelson, Adam; Warriner, Stuart L.; Wilson, Andrew J.

    ChemBioChem (2014), 15 (8), 1083-1087CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)

    The therapeutically relevant hypoxia inducible factor HIF-1α-p300 protein-protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in detg. potency. These small mols. represent the first biophys. characterized HIF-1α-p300 PPI inhibitors and the first examples of small-mol. arom. oligoamide helix mimetics to be shown to have a selective binding profile. Although the compds. were less potent than HIF-1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1α C-TAD from which it is derived.
16. 16

    Moon, H.; Lee, W. S.; Oh, M.; Lee, H.; Lee, J. H.; Im, W.; Lim, H. S. Design, Solid-Phase Synthesis, and Evaluation of a Phenyl-Piperazine-Triazine Scaffold as α-Helix Mimetics. ACS Comb. Sci. 2014, 16, 695– 701,  DOI: 10.1021/co500114f

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    Design, Solid-Phase Synthesis, and Evaluation of a Phenyl-Piperazine-Triazine Scaffold as α-Helix Mimetics

    Moon, Heejo; Lee, Woo Sirl; Oh, Misook; Lee, Huisun; Lee, Ji Hoon; Im, Wonpil; Lim, Hyun-Suk

    ACS Combinatorial Science (2014), 16 (12), 695-701CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)

    α-Helixes play a crit. role in mediating many protein-protein interactions (PPIs) as recognition motifs. Therefore, there is a considerable interest in developing small mols. that can mimic helical peptide segments to modulate α-helix-mediated PPIs. Due to the relatively low aq. soly. and synthetic difficulty of most current α-helix mimetic small mols., one important goal in this area is to develop small mols. with favorable physicochem. properties and ease of synthesis. Here we designed phenyl-piperazine-triazine-based α-helix mimetics, e.g. I, that possess improved water soly. and excellent synthetic accessibility. We developed a facile solid-phase synthetic route that allows for rapid creation of a large, diverse combinatorial library of α-helix mimetics. Further, we identified a selective inhibitor of the Mcl-1/BH3 interaction by screening a focused library of phenyl-piperazine-triazines, demonstrating that the scaffold is able to serve as functional mimetics of α-helical peptides. We believe that our phenyl-piperazine-triazine-based α-helix mimetics, along with the facile and divergent solid-phase synthetic method, have great potential as powerful tools for discovering potent inhibitors of given α-helix-mediated PPIs.
17. 17

    Tošovská, P.; Arora, P. S. Oligooxopiperazines as Nonpeptidic α-Helix Mimetics. Org. Lett. 2010, 12, 1588– 1591,  DOI: 10.1021/ol1003143

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    Oligooxopiperazines as Nonpeptidic α-Helix Mimetics

    Tosovska, Petra; Arora, Paramjit S.

    Organic Letters (2010), 12 (7), 1588-1591CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)

    A new class of nonpeptidic α-helix mimetics derived from α-amino acids and featuring chiral backbones is described. NMR and CD spectroscopies, in combination with mol. modeling studies, provide compelling evidence that oligooxopiperazine dimers adopt stable conformations that reproduce the arrangement of i, i+4, and i+7 residues on an α-helix.
18. 18

    Lao, B. B.; Drew, K.; Guarracino, D. A.; Brewer, T. F.; Heindel, D. W.; Bonneau, R.; Arora, P. S. Rational Design of Topographical Helix Mimics as Potent Inhibitors of Protein-Protein Interactions. J. Am. Chem. Soc. 2014, 136, 7877– 7888,  DOI: 10.1021/ja502310r

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    Rational Design of Topographical Helix Mimics as Potent Inhibitors of Protein-Protein Interactions

    Lao, Brooke Bullock; Drew, Kevin; Guarracino, Danielle A.; Brewer, Thomas F.; Heindel, Daniel W.; Bonneau, Richard; Arora, Paramjit S.

    Journal of the American Chemical Society (2014), 136 (22), 7877-7888CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small mol. scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Exptl. screening of focused compd. libraries is used to further optimize inhibitors but the no. of possible designs that can be efficiently synthesized and exptl. tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.
19. 19

    Rodriguez, A. L.; Tamrazi, A.; Collins, M. L.; Katzenellenbogen, J. A. Design, Synthesis, and in Vitro Biological Evaluation of Small Molecule Inhibitors of Estrogen Receptor α Coactivator Binding. J. Med. Chem. 2004, 47, 600– 611,  DOI: 10.1021/jm030404c

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    Design, Synthesis, and in Vitro Biological Evaluation of Small Molecule Inhibitors of Estrogen Receptor α Coactivator Binding

    Rodriguez, Alice L.; Tamrazi, Anobel; Collins, Margaret L.; Katzenellenbogen, John A.

    Journal of Medicinal Chemistry (2004), 47 (3), 600-611CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Nuclear receptors (NRs) complexed with agonist ligands activate transcription by recruiting coactivator protein complexes. In principle, one should be able to inhibit the transcriptional activity of the NRs by blocking this transcriptionally crit. receptor-coactivator interaction directly, using an appropriately designed coactivator binding inhibitor (CBI). To guide our design of various classes of CBIs, we have used the crystal structure of an agonist-bound estrogen receptor (ER) ligand binding domain (LBD) complexed with a coactivator peptide contg. the LXXLL signature motif bound to a hydrophobic groove on the surface of the LBD. One set of CBIs, based on an outside-in design approach, has various heterocyclic cores (triazenes, pyrimidines, trithianes, cyclohexanes) that mimic the tether sites of the three leucines on the peptide helix, onto which are appended leucine residue-like substituents. The other set, based on an inside-out approach, has a naphthalene core that mimics the two most deeply buried leucines, with substituents extending outward to mimic other features of the coactivator helical peptide. A fluorescence anisotropy-based coactivator competition assay was developed to measure the specific binding of these CBIs to the groove site on the ER-agonist complex with which coactivators interact; control ligand-binding assays assured that their interaction was not with the ligand binding pocket. The most effective CBIs were those from the pyrimidine family, the best binding with Ki values of ca. 30 μM. The trithiane- and cyclohexane-based CBIs appear to be poor structural mimics, because of equatorial vs. axial conformational constraints, and the triazene-based CBIs are also conformationally constrained by amine-substituent-to-ring resonance overlap, which is not the case with the higher affinity alkyl-substituted pyrimidines. The pyrimidine-based CBIs appear to be the first small mol. inhibitors of NR coactivator binding.
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    Becerril, J.; Hamilton, A. D. Helix Mimetics as Inhibitors of the Interaction of the Estrogen Receptor with Coactivator Peptides. Angew. Chem., Int. Ed. 2007, 46, 4471– 4473,  DOI: 10.1002/anie.200700657

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    Helix mimetics as inhibitors of the interaction of the estrogen receptor with coactivator peptides

    Becerril, Jorge; Hamilton, Andrew D.

    Angewandte Chemie, International Edition (2007), 46 (24), 4471-4473CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    The short and curlies: A new α-helix mimetic based on a pyridylpyridone scaffold has been developed to bind to the estrogen receptor (ER) by mimicking the key leucine side chains of coactivator LXXLL boxes (L = leucine, X = any amino acid). These inhibitors compete with coactivator peptides for the surface of the ER and act as small-mol. inhibitors of the ER-coactivator interaction.
21. 21

    Jacoby, E. Biphenyls as Potential Mimetics of Protein α-Helix. Bioorg. Med. Chem. Lett. 2002, 12, 891– 893,  DOI: 10.1016/S0960-894X(02)00031-8

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    Biphenyls as potential mimetics of protein α-helix

    Jacoby, Edgar

    Bioorganic & Medicinal Chemistry Letters (2002), 12 (6), 891-893CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)

    Based on theor. arguments, 2,6,3',5'-substituted biphenyl analogs are proposed as protein α-helix mimetics superimposing the side chains of the residues i, i+1, i+3 and i+4. Knowing that many protein-protein interactions of therapeutical relevance involve α-helix contacts, the communication outlines how this novel category of scaffolds might potentially open access to such targets.
22. 22

    Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X. Solid Supported High-Throughput Organic Synthesis of Peptide β-Turn Mimetics via Petasis Reaction/Diketopiperazine Formation. Tetrahedron Lett. 2000, 41, 4841– 4844,  DOI: 10.1016/S0040-4039(00)00669-9

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    Solid supported high-throughput organic synthesis of peptide β-turn mimetics via tandem Petasis reaction/diketopiperazine formation

    Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X.

    Tetrahedron Letters (2000), 41 (25), 4841-4844CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)

    High-throughput org. synthesis of bicyclic diketopiperazines, β-turn mimetics, is described. Starting from Merrifield resin-bound piperazine-2-carboxylate, first two side-chains are introduced via the Petasis reaction and subsequent amide bond formation. Unblocking the α-amino group of piperazine-2-carboxylate, Boc-N-protected α-amino acid coupling, and deprotection followed by cyclative cleavage introduces the remaining side-chains.
23. 23

    Mizuno, A.; Kameda, T.; Kuwahara, T.; Endoh, H.; Ito, Y.; Yamada, S.; Hasegawa, K.; Yamano, A.; Watanabe, M.; Arisawa, M.; Shuto, S. Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization. Chem. – Eur. J. 2017, 23, 3159– 3168,  DOI: 10.1002/chem.201605312

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    Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization

    Mizuno, Akira; Kameda, Tomoshi; Kuwahara, Tomoki; Endoh, Hideyuki; Ito, Yoshihiko; Yamada, Shizuo; Hasegawa, Kimiko; Yamano, Akihito; Watanabe, Mizuki; Arisawa, Mitsuhiro; Shuto, Satoshi

    Chemistry - A European Journal (2017), 23 (13), 3159-3168CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Detailed conformational analyses of the previously reported cyclopropane-based peptidomimetics and conformational anal.-driven ligand optimization are described. Computational calcns. and x-ray crystallog. showed that the characteristic features of cyclopropane function effectively to constrain the mol. conformation in a three-dimensionally diverse manner. Subsequent principal component anal. revealed that the diversity covers the broad chem. space filled by peptide secondary structures in terms of both main-chain and side-chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing nonpeptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target-binding conformation without requiring the three-dimensional structural information of the target and its peptide ligands.
24. 24

    Mizuno, A.; Matsui, K.; Shuto, S. From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane. Chem. – Eur. J. 2017, 23, 14394– 14409,  DOI: 10.1002/chem.201702119

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    From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

    Mizuno, Akira; Matsui, Kouhei; Shuto, Satoshi

    Chemistry - A European Journal (2017), 23 (58), 14394-14409CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug mols. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell-membrane permeability for targeting protein-protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomols. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chem. is described.
25. 25

    Ueda, H.; Kurita, J.; Neyama, H.; Hirao, Y.; Kouji, H.; Mishina, T.; Kasai, M.; Nakano, H.; Yoshimori, A.; Nishimura, Y. A Mimetic of the MSin3-Binding Helix of NRSF/REST Ameliorates Abnormal Pain Behavior in Chronic Pain Models. Bioorg. Med. Chem. Lett. 2017, 27, 4705– 4709,  DOI: 10.1016/j.bmcl.2017.09.006

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    25

    A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models

    Ueda, Hiroshi; Kurita, Jun-ichi; Neyama, Hiroyuki; Hirao, Yuuka; Kouji, Hiroyuki; Mishina, Tadashi; Kasai, Masaji; Nakano, Hirofumi; Yoshimori, Atsushi; Nishimura, Yoshifumi

    Bioorganic & Medicinal Chemistry Letters (2017), 27 (20), 4705-4709CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

    The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compds. to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examd. their ability to bind to mSin3 by NMR. One compd., mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chem. optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain.
26. 26

    Schoenherr, C. J.; Anderson, D. J. The Neuron-Restrictive Silencer Factor (NRSF): A Coordinate Repressor of Multiple Neuron-Specific Genes. Science 1995, 267, 1360– 1363,  DOI: 10.1126/science.7871435

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    The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes

    Schoenherr, Christopher; Anderson, David J.

    Science (Washington, D. C.) (1995), 267 (5202), 1360-3CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    The neuron-restrictive silencer factor (NRSF) binds a DNA sequence element, called the neuron-restrictive silencer element (NRSE), that represses neuronal gene transcription in nonneuronal cells. Consensus NRSEs have been identified in 18 neuron-specific genes. Complementary DNA clones encoding a functional fragment of NRSF were isolated and found to encode a novel protein contg. eight noncanonical zinc fingers. Expression of NRSF mRNA was detected in most nonneuronal tissues at several developmental stages. In the nervous system, NRSF mRNA was detected in undifferentiated neuronal progenitors, but not in differentiated neurons. NRSF represents the first example of a vertebrate silencer protein that potentially regulates a large battery of cell type-specific genes, and therefore may function as a master neg. regulator of neurogenesis.
27. 27

    Chong, J. A.; Tapia-Ramirez, J.; Kim, S.; Toledo-Aral, J. J.; Zheng, Y.; Boutros, M. C.; Altshuller, Y. M.; Frohman, M. A.; Kraner, S. D.; Mandel, G. REST: A Mammalian Silencer Protein That Restricts Sodium Channel Gene Expression to Neurons. Cell 1995, 80, 949– 957,  DOI: 10.1016/0092-8674(95)90298-8

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    REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons

    Chong, Jayhong A.; Tapia-Ramirez, Jose; Kim, Sandra; Toledo-Aral, Juan J.; Zheng, Yingcong; Boutros, Michael C.; Altshuller, Yelena M.; Frohman, Michael A.; Kraner, Susan D.; Mandel, Gail

    Cell (Cambridge, Massachusetts) (1995), 80 (6), 949-57CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    Expression of the type II voltage-dependent sodium channel gene is restricted to neurons by a silencer element active in nonneuronal cells. We have cloned cDNA coding for a transcription factor (REST) that binds to this silencer element. Expression of a recombinant REST protein confers the ability of silence type II reporter genes in neuronal cell types lacking the native REST protein, whereas expression of a dominant neg. form of REST in nonneuronal cells relieves silencing mediated by the native protein. REST transcripts in developing mouse embryos are detected ubiquitously mouse embryos are detected ubiquitously outside of the nervous system. We propose that expression of the type II sodium channel gene in neurons reflects a default pathway that is blocked in nonneuronal cells by the presence of REST.
28. 28

    Nomura, M.; Uda-Tochio, H.; Murai, K.; Mori, N.; Nishimura, Y. The Neural Repressor NRSF/REST Binds the PAH1 Domain of the Sin3 Corepressor by Using Its Distinct Short Hydrophobic Helix. J. Mol. Biol. 2005, 354, 903– 915,  DOI: 10.1016/j.jmb.2005.10.008

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    28

    The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix

    Nomura, Mitsuru; Uda-Tochio, Hiroko; Murai, Kiyohito; Mori, Nozomu; Nishimura, Yoshifumi

    Journal of Molecular Biology (2005), 354 (4), 903-915CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)

    In non-neuronal cells and neuronal progenitors, many neuron-specific genes are repressed by a neural restrictive silencer factor (NRSF)/repressor element 1 silencing transcription factor (REST), which is an essential transcriptional repressor recruiting the Sin3-HDAC complex. Sin3 contains four paired amphipathic helix (PAH) domains, PAH1, PAH2, PAH3 and PAH4. A specific target repressor for Sin3 is likely to bind to one of them independently. So far, only the tertiary structures of PAH2 domain complexes, when bound to the Sin3-interacting domains of Mad1 and HBP1, have been detd. Here, we reveal that the N-terminal repressor domain of NRSF/REST binds to the PAH1 domain of mSin3B, and det. the structure of the PAH1 domain assocd. with the NRSF/REST minimal repressor domain. Compared to the PAH2 structure, PAH1 holds a rather globular four-helix bundle structure with a semi-ordered C-terminal tail. In contrast to the amphipathic α-helix of Mad1 or HBP1 bound to PAH2, the short hydrophobic α-helix of NRSF/REST is captured in the cleft of PAH1. A nuclear hormone receptor corepressor, N-CoR has been found to bind to the PAH1 domain with a lower affinity than NRSF/REST by using its C-terminal region, which contains fewer hydrophobic amino acid residues than the NRSF/REST helix. For strong binding to a repressor, PAH1 seems to require a short α-helix consisting of mostly hydrophobic amino acid residues within the repressor. Each of the four PAH domains of Sin3 seems to interact with a characteristic helix of a specific repressor; PAH1 needs a mostly hydrophobic helix and PAH2 needs an amphipathic helix in each target repressor.
29. 29

    Kawase, H.; Ago, Y.; Naito, M.; Higuchi, M.; Hara, Y.; Hasebe, S.; Tsukada, S.; Kasai, A.; Nakazawa, T.; Mishina, T.; Kouji, H.; Takuma, K.; Hashimoto, H. MS-11, a Mimetic of the MSin3-Binding Helix in NRSF, Ameliorates Social Interaction Deficits in a Prenatal Valproic Acid-Induced Autism Mouse Model. Pharmacol. Biochem. Behav. 2019, 176, 1– 5,  DOI: 10.1016/j.pbb.2018.11.003

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    mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model

    Kawase, Haruki; Ago, Yukio; Naito, Megumi; Higuchi, Momoko; Hara, Yuta; Hasebe, Shigeru; Tsukada, Shinji; Kasai, Atsushi; Nakazawa, Takanobu; Mishina, Tadashi; Kouji, Hiroyuki; Takuma, Kazuhiro; Hashimoto, Hitoshi

    Pharmacology, Biochemistry and Behavior (2019), 176 (), 1-5CODEN: PBBHAU; ISSN:0091-3057. (Elsevier)

    Growing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examd. the effects of mS-11, a chem. optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphol. abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Addnl., we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA-exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine d. in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding.
30. 30

    Higo, J.; Takashima, H.; Fukunishi, Y.; Yoshimori, A. Generalized-Ensemble Method Study: A Helix-Mimetic Compound Inhibits Protein-Protein Interaction by Long-Range and Short-Range Intermolecular Interactions. J. Comput. Chem. 2021, 42, 956– 969,  DOI: 10.1002/jcc.26516

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    30

    Generalized-ensemble method study: A helix-mimetic compound inhibits protein-protein interaction by long-range and short-range intermolecular interactions

    Higo, Junichi; Takashima, Hajime; Fukunishi, Yoshifumi; Yoshimori, Atsushi

    Journal of Computational Chemistry (2021), 42 (14), 956-969CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    A heterocyclic compd. mS-11 is a helix-mimetic designed to inhibit binding of an intrinsic disordered protein neural restrictive silence factor/repressor element 1 silencing factor (NRSF/REST) to a receptor protein mSin3B. We apply a generalized ensemble method, multi-dimensional virtual-system coupled mol. dynamics developed by ourselves recently, to a system consisting of mS-11 and mSin3B, and obtain a thermally equilibrated distribution, which is comprised of the bound and unbound states extensively. The lowest free-energy position of mS-11 coincides with the NRSF/REST position in the exptl.-detd. NRSF/REST-mSin3B complex. Importantly, the mol. orientation of mS-11 is ordering in a wide region around mSin3B. The resultant binding scenario is: When mS-11 is distant from the binding site of mSin3B, mS-11 descends the free-energy slope toward the binding site maintaining the mol. orientation to be advantageous for binding. Then, finally a long and flexible hydrophobic sidechain of mS-11 fits into the binding site, which is the lowest-free-energy complex structure inhibiting NRSF/REST binding to mSin3B.
31. 31

    Ramachandran, G. N.; Sasisekharan, V. Conformation of Polypeptides and Proteins. Adv. Protein Chem. 1968, 23, 283– 437,  DOI: 10.1016/s0065-3233(08)60402-7

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    Conformation of polypeptides and proteins

    Ramachandran, G. N.; Sasisekharan, V.

    Advances in Protein Chemistry (1968), 23 (), 283-438CODEN: APCHA2; ISSN:0065-3233.

    A review. The stereochem. aspects of the problem are emphasized. 234 refs.
32. 32

    Hovmöller, S.; Zhou, T.; Ohlson, T. Conformations of Amino Acids in Proteins. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2002, 58, 768– 776,  DOI: 10.1107/S0907444902003359

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    Conformations of amino acids in proteins

    Hovmoller Sven; Zhou Tuping; Ohlson Tomas

    Acta crystallographica. Section D, Biological crystallography (2002), 58 (Pt 5), 768-76 ISSN:0907-4449.

    The main-chain conformations of 237 384 amino acids in 1042 protein subunits from the PDB were analyzed with Ramachandran plots. The populated areas of the empirical Ramachandran plot differed markedly from the classical plot in all regions. All amino acids in alpha-helices are found within a very narrow range of phi, psi angles. As many as 40% of all amino acids are found in this most populated region, covering only 2% of the Ramachandran plot. The beta-sheet region is clearly subdivided into two distinct regions. These do not arise from the parallel and antiparallel beta-strands, which have quite similar conformations. One beta region is mainly from amino acids in random coil. The third and smallest populated area of the Ramachandran plot, often denoted left-handed alpha-helix, has a different position than that originally suggested by Ramachandran. Each of the 20 amino acids has its own very characteristic Ramachandran plot. Most of the glycines have conformations that were considered to be less favoured. These results may be useful for checking secondary-structure assignments in the PDB and for predicting protein folding.
33. 33

    Garland, S. L.; Dean, P. M. Design Criteria for Molecular Mimics of Fragments of the β-Turn. 2. Cα-Cβ Bond Vector Analysis. J. Comput.-Aided. Mol. Des. 1999, 13, 485– 498,  DOI: 10.1023/A:1008014620568

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    Design criteria for molecular mimics of fragments of the β-turn. 2. Cα-Cβ bond vector analysis

    Garland, S. L.; Dean, P. M.

    Journal of Computer-Aided Molecular Design (1999), 13 (5), 485-498CODEN: JCADEQ; ISSN:0920-654X. (Kluwer Academic Publishers)

    In a previous paper, the authors have shown the utility of cluster anal. for identifying patterns in the way the Cα atoms of fragments of the β-turn are distributed in three dimensions. This work has been extended to the Cα-Cβ bond vectors of 2- and 3-side-chain fragments. Again, distinct patterns emerge and 10 and 12 classes of vector orientation have been identified for the 2- and 3-vector problem, resp. These clusters of vector distribution provide an optimal reduced set of design criteria for the de novo generation of novel peptidomimetic drugs for fragments of the β-turn.
34. 34

    Grabowski, K.; Proschak, E.; Baringhaus, K.; Rau, O.; Schubert-Xsilavecs, M.; Schneider, G. Bioisosteric Replacement of Molecular Scaffolds: From Natural Products to Synthetic Compounds. Nat. Prod. Commun. 2008, 3, 1355– 1360,  DOI: 10.1177/1934578X0800300821

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    Bioisosteric replacement of molecular scaffolds: from natural products to synthetic compounds

    Grabowski, Kristina; Proschak, Ewgenij; Baringhaus, Karl-Heinz; Rau, Oliver; Schubert-Zsilavecz, Manfred; Schneider, Gisbert

    Natural Product Communications (2008), 3 (8), 1355-1360CODEN: NPCACO; ISSN:1934-578X. (Natural Product Inc.)

    Natural products often contain scaffolds or core structures that prevent immediate synthetic accessibility. It is, therefore, desirable to find isosteric chemotypes that allow for scaffold-hopping or re-scaffolding. The idea is to obtain simpler chemotypes that are synthetically feasible and exhibit either the same or similar bioactivity as the original natural product or ref. compd. We developed and applied a virtual screening technique that represents a mol. scaffold by its side-chain attachment points (exit-vectors) and properties of the side-chain substituents. The technique was validated by retrospective screening for β-turn mimetics and HMG-CoA inhibitors. A prospective application aimed at finding new chemotypes of PPAR-α agonists. Two such compds. were found in a com. available screening compd. library yielding EC50 values in the low micromolar range. This study demonstrates the applicability of exit-vector based virtual screening to scaffold-hopping tasks.
35. 35

    Ballester, P. J.; Finn, P. W.; Richards, W. G. Ultrafast Shape Recognition: Evaluating a New Ligand-Based Virtual Screening Technology. J. Mol. Graphics Model. 2009, 27, 836– 845,  DOI: 10.1016/j.jmgm.2009.01.001

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    Ultrafast shape recognition: Evaluating a new ligand-based virtual screening technology

    Ballester, Pedro J.; Finn, Paul W.; Richards, W. Graham

    Journal of Molecular Graphics & Modelling (2009), 27 (7), 836-845CODEN: JMGMFI; ISSN:1093-3263. (Elsevier)

    Large scale database searching to identify mols. that share a common biol. activity for a target of interest is widely used in drug discovery. Such an endeavor requires the availability of a method encoding mol. properties that are indicative of biol. activity and at least one active mol. to be used as a template. Mol. shape was shown to be an important indicator of biol. activity; however, currently used methods are relatively slow, so faster and more reliable methods are highly desirable. Recently, a new non-superposition based method for mol. shape comparison, called Ultrafast Shape Recognition (USR), was devised with computational performance at least 3 orders of magnitude faster than previously existing methods. In this study, the authors investigate the performance of USR in retrieving biol. active compds. through retrospective Virtual Screening expts. Results show that USR performs better on av. than a com. available shape similarity method, while screening conformers at a rate that is more than 2500 times faster. This outstanding computational performance is particularly useful for searching much larger portions of chem. space than previously possible, which makes USR a very valuable new tool in the search for new lead mols. for drug discovery programs.
36. 36

    Kabsch, W.; Sander, C. Dictionary of Protein Secondary Structure: Pattern Recognition of Hydrogen-Bonded and Geometrical Features. Biopolymers 1983, 22, 2577– 2637,  DOI: 10.1002/bip.360221211

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    Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features

    Kabsch, Wolfgang; Sander, Christian

    Biopolymers (1983), 22 (12), 2577-637CODEN: BIPMAA; ISSN:0006-3525.

    For a successful anal. of the relation between amino acid sequence and protein structure, an unambiguous and phys. meaningful definition of secondary structure is essential. A set of simple and phys. motivated criteria for secondary structure, programmed as a pattern-recognition process of H-bonded and geometrical features extd. from x-ray coordinates were developed. Cooperative secondary structure is recognized as repeats of the elementary H-bonding patterns turn and bridge. Repeating turns are helixes, repeating bridges are ladders, connected ladders are sheets. Geometric structure is defined in terms of the concepts torsion and curvature of differential geometry. Local chain chirality is the torsional handedness of 4 consecutive Cα positions and is pos. for right-handed helixes and neg. for ideal twisted β-sheets. Curved pieces are defined as bends. Solvent exposure is given as the no. of H2O mols. in possible contact with a residue. The end result is a compilation of the primary structure, including SS bonds, secondary structure, and solvent exposure of 62 different globular proteins. The presentation is in linear form: strip graphs for an overall view and strip tables for the details of each of 10,925 residues. The dictionary is also available in computer-readable form for protein structure prediction work.
37. 37

    Touw, W. G.; Baakman, C.; Black, J.; Te Beek, T. A. H.; Krieger, E.; Joosten, R. P.; Vriend, G. A Series of PDB-Related Databanks for Everyday Needs. Nucleic Acids Res. 2015, 43, D364– D368,  DOI: 10.1093/nar/gku1028

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    A series of PDB-related databanks for everyday needs

    Touw, Wouter G.; Baakman, Coos; Black, Jon; te Beek, Tim A. H.; Krieger, E.; Joosten, Robbie P.; Vriend, Gert

    Nucleic Acids Research (2015), 43 (D1), D364-D368CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    We present a series of databanks that hold information that is computationally derived from Protein Data Bank (PDB) entries and that might augment macromol. structure studies. These derived databanks run parallel to the PDB, i.e. they have one entry per PDB entry. Several of the well-established databanks such as HSSP, PDBREPORT and PDB REDO have been updated and/or improved. The software that creates the DSSP databank, for example, has been rewritten to better cope with π-helixes. A large no. of databanks have been added to aid computational structural biol.; some examples are lists of residues that make crystal contacts, lists of contacting residues using a series of contact definitions or lists of residue accessibilities. PDB files are not the optimal presentation of the underlying data for many studies. We therefore made a series of databanks that hold PDB files in an easier to use or more consistent representation. The BDB databank holds X-ray PDB files with consistently represented B-factors.We also added several visualization tools to aid the users of our databanks.
38. 38

    Ballester, P. J.; Westwood, I.; Laurieri, N.; Sim, E.; Richards, W. G. Prospective Virtual Screening with Ultrafast Shape Recognition: The Identification of Novel Inhibitors of Arylamine N-Acetyltransferases. J. R. Soc. Interface 2010, 7, 335– 342,  DOI: 10.1098/rsif.2009.0170

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    Prospective virtual screening with Ultrafast Shape Recognition: the identification of novel inhibitors of arylamine N-acetyltransferases

    Ballester, Pedro J.; Westwood, Isaac; Laurieri, Nicola; Sim, Edith; Richards, W. Graham

    Journal of the Royal Society, Interface (2010), 7 (43), 335-342CODEN: JRSICU; ISSN:1742-5689. (Royal Society)

    There is currently a shortage of chem. mols. that can be used as bioactive probes to study mol. targets and potentially as starting points for drug discovery. One inexpensive way to address this problem is to use computational methods to screen a comprehensive database of small mols. to discover novel structures that could lead to alternative and better bioactive probes. Despite that pleasing logic the results have been somewhat mixed. Here we describe a virtual screening technique based on ligand-receptor shape complementarity, Ultrafast Shape Recognition (USR). USR is specifically applied to identify novel inhibitors of arylamine N-acetyltransferases by computationally screening almost 700 million mol. conformers in a time- and resource-efficient manner. A small no. of the predicted active compds. were purchased and tested obtaining a confirmed hit rate of 40% which is an outstanding result for a prospective virtual screening.
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    Hehre, W.; Klunzinger, P.; Deppmeier, B.; Driessen, A.; Uchida, N.; Hashimoto, M.; Fukushi, E.; Takata, Y. Efficient Protocol for Accurately Calculating ¹³C Chemical Shifts of Conformationally Flexible Natural Products: Scope, Assessment, and Limitations. J. Nat. Prod. 2019, 82, 2299– 2306,  DOI: 10.1021/acs.jnatprod.9b00603

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    Efficient Protocol for Accurately Calculating 13C Chemical Shifts of Conformationally Flexible Natural Products: Scope, Assessment, and Limitations

    Hehre, Warren; Klunzinger, Phillip; Deppmeier, Bernard; Driessen, Andy; Uchida, Noritaka; Hashimoto, Masaru; Fukushi, Eri; Takata, Yusuke

    Journal of Natural Products (2019), 82 (8), 2299-2306CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)

    An efficient protocol for calcg. 13C NMR chem. shifts for natural products with multiple degrees of conformational freedom is described. This involves a multistep procedure starting from mol. mechanics and ending with a large basis set d. functional model to obtain accurate Boltzmann conformer wts., followed by empirically cor. d. functional NMR calcns. for the individual conformers. The accuracy of the protocol (av. rms <4 ppm) was detd. by application to ∼925 diverse natural products, the structures of which have been confirmed either by X-ray crystallog. or independent synthesis. The protocol was then applied to ∼ 2275 natural products, the structures of which were elucidated mainly by NMR and MS data. Five to ten percent of the latter compds. exhibited rms errors significantly in excess of 4 ppm, suggesting possible structural or signal assignment errors. Both data sets are available from an online browser (NMR.wavefun.com). The procedure can be and has been fully automated and is practical using present-generation personal computers, requiring a few hours or days depending on the size of the mol. and no. of accessible conformers.