globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1703287114
论文题名:
Testing inhomogeneous solvation theory in structure-based ligand discovery
作者: Balius T.E.; Fischer M.; Stein R.M.; Adler T.B.; Nguyen C.N.; Cruz A.; Gilson M.K.; Kurtzman T.; Shoichet B.K.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2017
卷: 114, 期:33
起始页码: E6839
结束页码: E6846
语种: 英语
英文关键词: Docking ; Inhomogeneous solvation theory ; Ligand discovery ; Structure-based drug design ; Water
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
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.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163804
Appears in Collections:气候变化与战略

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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., Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA 92093, United States; Kurtzman, T., 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, Ph.D. Program in Biochemistry, Graduate Center, City University of New York, New York, NY 10016, United States; Shoichet, B.K., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, United States

Recommended Citation:
Balius T.E.,Fischer M.,Stein R.M.,et al. Testing inhomogeneous solvation theory in structure-based ligand discovery[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(33)
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