Molecular dynamics simulation studies of GSK-3β ATP competitive inhibitors: understanding the factors contributing to selectivity

Arfeen, Minhajul ; Patel, Rahul ; Khan, Tosif ; Bharatam, Prasad V. (2015) Molecular dynamics simulation studies of GSK-3β ATP competitive inhibitors: understanding the factors contributing to selectivity Journal of Biomolecular Structure and Dynamics, 33 (12). pp. 2578-2593. ISSN 0739-1102

Full text not available from this repository.

Official URL: http://doi.org/10.1080/07391102.2015.1063457

Related URL: http://dx.doi.org/10.1080/07391102.2015.1063457

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.

Item Type:Article
Source:Copyright of this article belongs to FOIA Privacy.
Keywords:CDK-2; GSK-3; Amino Acids; Molecular Docking; Molecular Dynamics.
ID Code:116401
Deposited On:12 Apr 2021 09:31
Last Modified:12 Apr 2021 09:31

Repository Staff Only: item control page