期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：E8051-E8058
DOI：10.1073/pnas.1615932113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceProtein-protein interfaces have become an emerging class of molecular targets for the design of therapeutic drugs. However, major challenges exist for the correct identification of binding sites on the protein surface as well as drug-like modulators of protein-protein interaction. An integrated approach using molecular fragment docking and coevolutionary analysis is presented to face these challenges. This approach can accurately predict and characterize the binding sites for protein-protein interactions as well as provide clusters of bound, fragment-sized molecules on the druggable regions of the predicted binding site. These bound, molecular fragments can be chemically combined to create candidate drugs. 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.
关键词：protein−protein interface ; druggable surface ; hot spots ; direct coupling analysis ; drug design
