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

doi:10.1073/pnas.1615932113

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis
	Bai, Fang 1; Morcos, Faruck 2,3,4; Cheng, Ryan R.1; Jiang, Hualiang5 ; Onuchic, Jose N.1,6,7,8
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2016-12-13
卷号	113 期号:50 页码:E8051-E8058
关键词	protein-protein interface druggable surface hot spots direct coupling analysis drug design
ISSN号	0027-8424
DOI	10.1073/pnas.1615932113
文献子类	Article
英文摘要	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.
资助项目	National Science Foundation[PHY-1427654] ; National Science Foundation[CHE-1614101] ; National Science Foundation[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] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[91313000]
WOS关键词	DRUG DISCOVERY ; HIV-1 PROTEASE ; BINDING-SITES ; WEB SERVER ; COMPUTATIONAL PREDICTION ; BREAST-CANCER ; HOT-SPOTS ; RESIDUES ; CDK1 ; DIMERIZATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000389696700007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275765]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Jiang, Hualiang; Onuchic, Jose N.
作者单位	1.Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA; 2.Univ Texas Dallas, Dept Biol Sci, Dallas, TX 75080 USA; 3.Univ Texas Dallas, Dept Bioengn, Dallas, TX 75080 USA; 4.Univ Texas Dallas, Ctr Syst Biol, Dallas, TX 75080 USA; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 6.Rice Univ, Dept Phys & Astron, Houston, TX 77005 USA; 7.Rice Univ, Dept Chem, Houston, TX 77005 USA; 8.Rice Univ, Dept Biosci, Houston, TX 77005 USA
推荐引用方式 GB/T 7714	Bai, Fang,Morcos, Faruck,Cheng, Ryan R.,et al. Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2016,113(50):E8051-E8058.
APA	Bai, Fang,Morcos, Faruck,Cheng, Ryan R.,Jiang, Hualiang,&Onuchic, Jose N..(2016).Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,113(50),E8051-E8058.
MLA	Bai, Fang,et al."Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.50(2016):E8051-E8058.