Identification of novel dual inhibitors targeting XOR and URAT1 via multiple virtual screening methods

Abstract

The clinically applicable single uric acid transporter 1 (URAT1) inhibitor or xanthine oxidoreductase (XOR) inhibitor cannot solve the clinical needs in anti-hyperuricemia well. It is expected that combined inhibition of both XOR and URAT1 might effectively decrease the level of uric acid and avoid the issue of insufficient potency by single-target drugs. 3D-QSAR pharmacophore modeling, molecular docking, and ADMET filtering were applied for potential dual inhibitors. And top-ranked three compounds were selected to MD simulation analysis, with utilization of binding free energy and decomposition data. 4917-2281, 4109-2078 and C301-8913, have potential inhibitory potency for both XOR and URAT1 and were suitable for further experimental analysis and modification.