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Molecular modelling studies of 3,5-dipyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors using 3D-QSAR, Topomer CoMFA, molecular docking and molecular dynamic simulations
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DOI：10.1016/j.jtice.2016.09.018.png)
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Abstract
En 中文
Xanthine oxidoreductase is the key enzyme that catalyses hypoxanthine to uric acid coupled with the generation of reactive oxygen species, which is closely related with a variety of diseases, such as gout, hyperuricemia, and cardiovascular diseases. In this work, a series of xanthine oxidoreductase inhibitors were studied by a combination of molecular modelling techniques including: three-dimensional quantitative structure-activity relationship (3D-QSAR), Topomer comparative molecular field analysis (CoMFA), molecular docking, and molecular dynamic simulations. The best CoMFA model afforded a leave-one-out correlation coefficient (q(2)) and a non-validated correlation coefficient (r(2)) of 0.578 and 0.988, respectively. The best comparative molecular similarity indices analysis (CoMSIA) model provided a q(2) of 0.631 and an r(2) value of 0.966. The analysis of Topomer CoMFA model gave q(2) = 0.698 and r(2) = 0.907, which indicated that the model had a good predictive ability. The results suggested that the steric, electrostatic, and hydrophobic fields played an important role in the models. The structure-activity relationship was summarised and a small amount of new derivatives were designed with better predictive activities. Meanwhile, molecular docking and molecular dynamic simulations were performed to further elucidate the proposed docking conformations for the inhibitors binding to the protein. (C) 2016 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
Keywords:
Xanthine oxidoreductase inhibitor
3D-QSAR
Topomer CoMFA
Molecular docking
Molecular dynamic simulations
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