title: Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis.
abstract: Protein-protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein-protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular docking-based screen. (ii) The energetically favorable binding sites of the probes, called hot spots, are spatially clustered to map out candidate binding sites on the protein surface. (iii) A coevolution-based interface interaction score is used to discriminate between different candidate binding sites, yielding potential interfacial targets for therapeutic drug design. This approach is validated for important, well-studied disease-related proteins with known pharmaceutical targets, and also identifies targets that have yet to be studied. Moreover, therapeutic agents are proposed by chemically connecting the fragments that are strongly bound to the hot spots.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Dallas, TX 75080.|Department of Bioengineering, University of Texas at Dallas, Dallas, TX 75080.|Center for Systems Biology, University of Texas at Dallas, Dallas, TX 75080.
authors.forename: Faruck
authors.initials: F
authors.lastname: Morcos
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Cheng
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; jonuchic@rice.edu hljiang@mail.simm.ac.cn.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; jonuchic@rice.edu hljiang@mail.simm.ac.cn.|Department of Physics and Astronomy, Rice University, Houston, TX 77005.|Department of Chemistry, Rice University, Houston, TX 77005.|Department of Biosciences, Rice University, Houston, TX 77005.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D015195:Drug Design; D019143:Evolution, Molecular; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D006655:Histone Deacetylases / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D015335:Molecular Probes; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects
chemical_list: C093090:CKS1B protein, human; D017320:HIV Protease Inhibitors; D015335:Molecular Probes; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C528899:CDK1 protein, human; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
keywords: direct coupling analysis; drug design; druggable surface; hot spots; protein−protein interface