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

• Published in: Journal of molecular structure 2022-05, Vol.1256, p.132567, Article 132567
• Main Authors: Zhu, XinYing, Yang, Chao, Zhang, Lei, Li, Jing
• Format: Article
• Language: English
• Subjects: Anti-hyperuricemia; Binding free energy; Dual inhibitors; Molecular dynamics; Virtual screening
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.132567

•Multiple methods in silico were implemented to find potential novel dual-inhibitors targeting XOR and URAT1.•Analysis of the binding modes with top-ranked three compounds and reference compounds, revealed the same binding pocket and similar interactions with key residues in target proteins.•MD simulation of top-ranked three compounds revealed that all complexes were stable in the active sites of the target proteins.•MM-PBSA calculations further indicated good binding affinity of three compounds to the target proteins. These theoretical studies provide a strong basis for the design of efficient dual inhibitors and further experiments. 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. [Display omitted]