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Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies.
Comb Chem High Throughput Screen. 2016; 19(4):298-306.CC

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+Show Affiliations

Hossain T
No affiliation info available
Saha A
Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata-700009, India. achintya_saha@yahoo.com.
Mukherjee A
No affiliation info available

MeSH

Alzheimer DiseaseCatalytic DomainGlycogen Synthase Kinase 3 betaHumansHydrogen BondingLigandsModels, MolecularProtein BindingProtein ConformationQuantitative Structure-Activity RelationshipStatic Electricity

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27064095

Citation

Hossain, Tabassum, et al. "Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies." Combinatorial Chemistry & High Throughput Screening, vol. 19, no. 4, 2016, pp. 298-306.
Hossain T, Saha A, Mukherjee A. Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies. Comb Chem High Throughput Screen. 2016;19(4):298-306.
Hossain, T., Saha, A., & Mukherjee, A. (2016). Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies. Combinatorial Chemistry & High Throughput Screening, 19(4), 298-306.
Hossain T, Saha A, Mukherjee A. Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies. Comb Chem High Throughput Screen. 2016;19(4):298-306. PubMed PMID: 27064095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploring Structural and Physicochemical Profiles of Potential GSK-3β Inhibitors Using Structure- and Ligand-Based Modeling Studies. AU - Hossain,Tabassum, AU - Saha,Achintya, AU - Mukherjee,Arup, PY - 2015/09/15/received PY - 2016/02/25/revised PY - 2016/03/10/accepted PY - 2016/4/12/entrez PY - 2016/4/12/pubmed PY - 2017/7/29/medline SP - 298 EP - 306 JF - Combinatorial chemistry & high throughput screening JO - Comb Chem High Throughput Screen VL - 19 IS - 4 N2 - 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. SN - 1875-5402 UR - https://www.unboundmedicine.com/medline/citation/27064095/Exploring_Structural_and_Physicochemical_Profiles_of_Potential_GSK_3��_Inhibitors_Using_Structure__and_Ligand_Based_Modeling_Studies_ DB - PRIME DP - Unbound Medicine ER -