Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies

Author(s): Tabassum Hossain, Achintya Saha, Arup Mukherjee

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 19 , Issue 4 , 2016

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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 R2 = 0.965, se = 0.212, Q2 = 0.525, R2pred = 0.709, r2m = 0.579 and CoMSIA: R2 = 0.935, se = 0.289, Q2 = 0.581, R2pred = 0.723, r2m = 0.935, that explain the importance of steric, electrostatic, hydrogen bond (HB) acceptor of the molecule for inhibition of GSK-3β. The HQSAR study (R2 = 0.871, se = 0.400, Q2 = 0.639, R2pred = 0.721, r2m = 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.

Keywords: GSK-3β, CoMFA, CoMSIA, HQSAR, pharmacophore mapping, e-pharmacophore.

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Article Details

VOLUME: 19
ISSUE: 4
Year: 2016
Page: [298 - 306]
Pages: 9
DOI: 10.2174/1386207319666160411125646
Price: $65

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