Studies of febuxostat analogues as xanthine oxidase inhibitors through 3D-QSAR, Topomer CoMFA and molecular modeling

Xanthine oxidase, a complex molybdoflavoprotein, catalyzes the hydroxylation of xanthine to uric acid, which has emerged as an important target for gout and hyperuricemia. In this work, a combination of molecular modeling methods was performed on a series of febuxostat analogues as xanthine oxidase inhibitors to establish molecular models for new drug design, including three-dimensional quantitative structure-activity relationship, topomer comparative molecular field analysis (CoMFA), molecular docking and molecular dynamic simulations. The optimal CoMFA model yielded a leave-one-out correlation coefficient (q(2)) of 0.841 and a non-validated correlation coefficient (r(2)) of 0.985. The respective q(2) and r(2) of the best comparative molecular similarity indices analysis (CoMSIA) model were 0.794 and 0.972, respectively. The Topomer CoMFA model provided a q(2) of 0.915 and an r(2) of 0.977. 3D contour maps generated from CoMFA and CoMSIA have identified several key features responsible for the inhibition activity. Molecular modeling was taken to further elucidate the proposed binding conformations of the inhibitors to the protein. The obtained results can be served as a useful guideline for designing novel febuxostat derivatives with improved activity against xanthine oxidase.