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3D-Qsar, Molecular Docking, and Molecular Dynamic Simulations for Prediction of New Hsp90 Inhibitors Based on Isoxazole Scaffold Publisher Pubmed



Abbasi M1 ; Sadeghialiabadi H1 ; Amanlou M2
Authors
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Authors Affiliations
  1. 1. Faculty of Pharmacy, Department of Medicinal Chemistry, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  2. 2. Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Biomolecular Structure and Dynamics Published:2018


Abstract

Heat shock protein 90(Hsp90), as a molecular chaperone, play a crucial role in folding and proper function of many proteins. Hsp90 inhibitors containing isoxazole scaffold are currently being used in the treatment of cancer as tumor suppressers. Here in the present studies, new compounds based on isoxazole scaffold were predicted using a combination of molecular modeling techniques including three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamic (MD) simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were also done. The steric and electrostatic contour map of CoMFA and CoMSIA were created. Hydrophobic, hydrogen bond donor and acceptor of CoMSIA model also were generated, and new compounds were predicted by CoMFA and CoMSIA contour maps. To investigate the binding modes of the predicted compounds in the active site of Hsp90, a molecular docking simulation was carried out. MD simulations were also conducted to evaluate the obtained results on the best predicted compound and the best reported Hsp90 inhibitors in the 3D-QSAR model. Findings indicate that the predicted ligands were stable in the active site of Hsp90. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
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