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Role of bridging water molecules in GSK3β‐inhibitor complexes: Insights from QM/MM, MD, and molecular docking studies
Author(s) -
Lu ShaoYong,
Jiang YongJun,
Lv Jing,
Zou JianWei,
Wu TianXing
Publication year - 2011
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21775
Subject(s) - oniom , qm/mm , docking (animal) , chemistry , molecular dynamics , hydrogen bond , molecule , molecular mechanics , computational chemistry , affinities , bridging (networking) , stereochemistry , molecular model , organic chemistry , medicine , computer network , nursing , computer science
The role of water molecules is increasingly gaining interest in drug design, and several studies have highlighted their paramount contributions to the specificity and the affinity of ligand binding. In this study, we employ the two‐layer ONIOM‐based quantum mechanics/molecular mechanics (QM/MM) calculations, molecular dynamics (MD) simulations, and molecular docking studies to investigate the effect of bridging water molecules at the GSK3β‐inhibitors interfaces. The results obtained from the ONIOM geometry optimization and AIM analysis corroborated the presence of bridging water molecules that form hydrogen bonds with protein side chain of Thr138 and/or backbone of Gln185, and mediate interactions with inhibitors in the 10 selected GSK3β‐inhibitor complexes. Subsequently, MD simulations carried out on a representative system of 1R0E demonstrated that the bridging water molecule is stable at the GSK3β‐inhibitor interface and appears to contribute to the stability of the protein–inhibitor interactions. Furthermore, molecular docking studies of GSK3β‐inhibitor complexes indicated that the inhibitors can increase binding affinities and the better docked conformation of inhibitors can be obtained by inclusion of the bridging water molecules, especially for the flexible inhibitors, in docking experiments into individual protein conformations. Our results elucidate the importance of bridging water molecules at the GSK3β‐inhibitor interfaces and suggest that they might prove useful in rational drug design. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011

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