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Theoretical studies on the selective mechanisms of GSK 3β and CDK 2 by molecular dynamics simulations and free energy calculations
Author(s) -
Zhao Sufang,
Zhu Jingyu,
Xu Lei,
Jin Jian
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12907
Subject(s) - gsk 3 , molecular dynamics , docking (animal) , cyclin dependent kinase , kinase , umbrella sampling , drug design , chemistry , rational design , threonine , binding site , serine , cyclin dependent kinase 2 , computational biology , biochemistry , protein kinase a , biology , phosphorylation , computational chemistry , cell , cell cycle , genetics , medicine , nursing
Glycogen synthase kinase 3 ( GSK 3) is a serine/threonine protein kinase which is widely involved in cell signaling and controls a broad number of cellular functions. GSK 3 contains α and β isoforms, and GSK 3β has received more attention and becomes an attractive drug target for the treatment of several diseases. The binding pocket of cyclin‐dependent kinase 2 ( CDK 2) shares high sequence identity to that of GSK 3β, and therefore, the design of highly selective inhibitors toward GSK 3β remains a big challenge. In this study, a computational strategy, which combines molecular docking, molecular dynamics simulations, free energy calculations, and umbrella sampling simulations, was employed to explore the binding mechanisms of two selective inhibitors to GSK 3β and CDK 2. The simulation results highlighted the key residues critical for GSK 3β selectivity. It was observed that although GSK 3β and CDK 2 share the conserved ATP ‐binding pockets, some different residues have significant contributions to protein selectivity. This study provides valuable information for understanding the GSK 3β‐selective binding mechanisms and the rational design of selective GSK 3β inhibitors.