期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 50, 页码 E8051-E8058出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1615932113
关键词
protein-protein interface; druggable surface; hot spots; direct coupling analysis; drug design
资金
- National Science Foundation [PHY-1427654, CHE-1614101, MCB-1241332]
- Cancer Prevention and Research Institute of Texas [R1110]
- Welch Foundation Grant [C-1792]
- National Basic Research Program of China [2015CB910304]
- National Natural Science Foundation of China [21210003, 81230076, 91313000]
- Direct For Mathematical & Physical Scien
- Division Of Physics [1427654] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1241332, 1614101] Funding Source: National Science Foundation
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 computationalmethod to estimate druggable protein-protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular dockingbased 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.
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