title: Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies.
abstract: Glycogen synthase kinase-3β (GSK-3β) is a promising target for therapeutic invasion of Alzheimer's disease (AD). The kinase enzyme plays major role in pathological process for the formation of β-amyloid plaques and neurofibrillary tangles in AD. In the present study, structure-based pharmacophore and ligand-based 3D QSAR, HQSAR and pharmacophore mapping studies have been emphasized to explore the possible structural requirement of this potential kinase inhibitors using a structurally diverse set of compounds. The developed models were validated with the interaction study at the catalytic cleft. The 3D QSAR studies yield robust models of CoMFA R(2) = 0.965, se = 0.212, Q(2) = 0.525, R(2)pred = 0.709, r(2)m = 0.579 and CoMSIA: R(2) = 0.935, se = 0.289, Q(2) = 0.581, R(2)pred = 0.723, r(2)m = 0.935, that explain the importance of steric, electrostatic, hydrogen bond (HB) acceptor of the molecule for inhibition of GSK-3β. The HQSAR study (R(2) = 0.871, se = 0.400, Q(2) = 0.639, R(2)pred = 0.721, r(2)m = 0.664) indicated the fragments of the molecular fingerprints that might be important for inhibition. Both structure- and ligand-based pharmacophore mapping proposed that acceptor and donor features of the molecule are essential for receptor-ligand interactions. Molecular diversity provides an opportunity on wide range of applicability for the GSK-3β inhibitors, and depicts information on the structural and properties requirement for effective binding at the active site selectivity that minimize the side effects with therapeutic benefits.
authors.forename: Tabassum
authors.initials: T
authors.lastname: Hossain
authors.affiliation: Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata-700009, India. achintya_saha@yahoo.com.
authors.forename: Achintya
authors.initials: A
authors.lastname: Saha
authors.forename: Arup
authors.initials: A
authors.lastname: Mukherjee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D020134:Catalytic Domain; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
chemical_list: D008024:Ligands; D000071679:Glycogen Synthase Kinase 3 beta