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

A B S T R A C T 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 inhi-bition 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 se-lected 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.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study aimed to find compounds with dual XOR and URAT1 inhibitory activity to address the issue of insufficient potency by single-target drugs. Multiple computational methods were used to screen and evaluate potential dual inhibitors.