title: Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations.
abstract: Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase which is widely involved in cell signaling and controls a broad number of cellular functions. GSK3 contains α and β isoforms, and GSK3β has received more attention and becomes an attractive drug target for the treatment of several diseases. The binding pocket of cyclin-dependent kinase 2 (CDK2) shares high sequence identity to that of GSK3β, and therefore, the design of highly selective inhibitors toward GSK3β 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 GSK3β and CDK2. The simulation results highlighted the key residues critical for GSK3β selectivity. It was observed that although GSK3β and CDK2 share the conserved ATP-binding pockets, some different residues have significant contributions to protein selectivity. This study provides valuable information for understanding the GSK3β-selective binding mechanisms and the rational design of selective GSK3β inhibitors.
authors.affiliation: Department of Gastroenterology, The 2nd Hospital of Shenzhen (The First Affiliated Hospital of Shenzhen University), ShenZhen, Guangdong, China.
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D000071679:Glycogen Synthase Kinase 3 beta; D051357:Cyclin-Dependent Kinase 2
keywords: Glycogen synthase kinase 3 (GSK3); cyclin-dependent kinase 2 (CDK2); free energy calculations; molecular dynamics simulations; selectivity