Journal
JOURNAL OF MOLECULAR STRUCTURE
Volume 1256, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.molstruc.2022.132567
Keywords
Anti-hyperuricemia; Dual inhibitors; Virtual screening; Molecular dynamics; Binding free energy
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Funding
- Key-Area Research and Development Program of Guangdong Province [2020B010188001]
- Science and Technology Project of Guangzhou [202102080325]
- Hebei Province Key Laboratory of Traditional Chinese Medicine Research and Development [ZYKF202001]
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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.
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.
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