气候变化领域集成服务门户(CCPortal): Testing inhomogeneous solvation theory in structure-based ligand discovery

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DOI	10.1073/pnas.1703287114
	Testing inhomogeneous solvation theory in structure-based ligand discovery
	Balius T.E.; Fischer M.; Stein R.M.; Adler T.B.; Nguyen C.N.; Cruz A.; Gilson M.K.; Kurtzman T.; Shoichet B.K.
发表日期	2017
ISSN	0027-8424
起始页码	E6839
结束页码	E6846
卷号	114 期号:33
英文摘要	Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST’s impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies. © 2017, National Academy of Sciences. All rights reserved.
英文关键词	Docking; Inhomogeneous solvation theory; Ligand discovery; Structure-based drug design; Water
语种	英语
scopus关键词	ligand; water; protein binding; solvent; water; Article; crystal structure; enthalpy; hydrogen bond; hydrophilicity; inhomogeneous solvation theory; ligand binding; molecular docking; molecular dynamics; molecular recognition; priority journal; protein binding; solvation; structure activity relation; algorithm; binding site; biology; chemical structure; chemistry; kinetics; procedures; protein conformation; solution and solubility; thermodynamics; X ray crystallography; Algorithms; Binding Sites; Computational Biology; Crystallography, X-Ray; Kinetics; Ligands; Molecular Docking Simulation; Molecular Structure; Protein Binding; Protein Conformation; Solutions; Solvents; Thermodynamics; Water
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160602
作者单位	Balius, T.E., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, United States; Fischer, M., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, United States, Department of Chemical Biology and Therapeutics, Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States; Stein, R.M., Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, CA 94158, United States; Adler, T.B., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, United States; Nguyen, C.N., Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA 92093, United States; Cruz, A., Department of Chemistry, Lehman College, Bronx, NY 10468, United States, Ph.D. Program in Chemistry, Graduate Center, City University of New York, New York, NY 10016, United States; Gilson, M.K., Skagg...
推荐引用方式 GB/T 7714	Balius T.E.,Fischer M.,Stein R.M.,et al. Testing inhomogeneous solvation theory in structure-based ligand discovery[J],2017,114(33).
APA	Balius T.E..,Fischer M..,Stein R.M..,Adler T.B..,Nguyen C.N..,...&Shoichet B.K..(2017).Testing inhomogeneous solvation theory in structure-based ligand discovery.Proceedings of the National Academy of Sciences of the United States of America,114(33).
MLA	Balius T.E.,et al."Testing inhomogeneous solvation theory in structure-based ligand discovery".Proceedings of the National Academy of Sciences of the United States of America 114.33(2017).