Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis

Fang Bai, Faruck Morcos, Ryan R. Cheng, Hualiang Jiang, José N. Onuchic

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish
Pages (from-to)E8051-E8058
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016

Keywords

  • Direct coupling analysis
  • Drug design
  • Druggable surface
  • Hot spots
  • Protein-protein interface

ASJC Scopus subject areas

  • General

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