Combined pharmacophore-guided 3D-QSAR, molecular docking and molecular dynamics studies for evodiamine analogs as DNA topoisomerase I inhibitors

DNA topoisomerase I (TopoI) is a new important anti-cancer drug target. Pharmacophore, 3D-QSAR, molecular docking and molecular dynamics studies were used to reveal structural and chemical features essential for evodiamine and designing/screening novel and potent inhibitors. The best pharmacophore model consists of four hydrophobic interaction sites and three hydrogen bond receptors. 60 evodiamine analogs were used for constructing the best comparative molecular field analysis (CoMFA, q(2) = 0.729, r(2) = 0.985) and comparative molecular similarity index analysis (CoMSIA, q(2) = 0.746, r(2) = 0.989) models, the models had high predictive ability, and the contour map was in good agreement with the generated pharmacophore features. Through virtual screening and structure-activity relationship (SAR), we obtained ten(DS1-8, z1-2) well predicted compounds. By molecular docking and molecular dynamics, we found the electrostatic field had the greatest influence on the residues ASN722 and THR718 in the DNA minor groove and the molecular structure should be planarized and appropriate in this region. The hydrogen bond produced by the inhibitor with the residues GLU356 and ARG364 and the hydrophobic interaction with base TGP11, DA113 play an important role in protein stability of the inhibitors. Results provide favorable theoretical foundation for further structural optimization, design, and synthesis of novel DNA Topol inhibitor. (C) 2017 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.