title: Molecular dynamics simulation studies of GSK-3β ATP competitive inhibitors: understanding the factors contributing to selectivity.
abstract: Glycogen synthase kinase-3 is a constitutively acting, multifunctional serine threonine kinase, the role of which has been implicated in several physiological pathways and has emerged as a promising target for the treatment of type-II diabetes and Alzheimer's disease. In order to provide a detailed understanding of the origin of selectivity determinants of ATP competitive inhibitors, molecular dynamics simulations in combination with MM-PBSA binding energy calculations were performed using crystal structures of GSK-3β and CDK-2 in complex with 12 ATP competitive inhibitors. Analysis of energy contributions indicate that electrostatic interaction energy dictates the selectivity of ATP competitive inhibitors against CDK-2. Key interactions as well as residues that potentially make a major contribution to the binding free energy were identified at the ATP binding site. This analysis stresses the need for the inhibitors to interact with Lys85, Thr138, and Arg141 in the binding site of GSK-3β to show selectivity. The residue-wise energy decomposition analysis further suggested the additional role of Gln185 in determining the selectivity of maleimides. The results obtained in this study can be utilized to design new selective GSK-3 ATP competitive inhibitors.
authors.affiliation: a Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar, Punjab 160062 , India.
authors.forename: Minhajul
authors.initials: M
authors.lastname: Arfeen
authors.affiliation: a Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar, Punjab 160062 , India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Patel
authors.affiliation: a Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar, Punjab 160062 , India.
authors.forename: Tosif
authors.initials: T
authors.lastname: Khan
authors.affiliation: a Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar, Punjab 160062 , India.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Bharatam
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000465:Algorithms; D001665:Binding Sites; D001667:Binding, Competitive; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: CDK-2; GSK-3; amino acids; molecular docking; molecular dynamics