Abstract
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 (q2) and a non-validated correlation coefficient (r2) of 0.578 and 0.988, respectively. The best comparative molecular similarity indices analysis (CoMSIA) model provided a q2 of 0.631 and an r2 value of 0.966. The analysis of Topomer CoMFA model gave q2=0.698 and r2=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.
Published Version
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