Discovery of Natural Multitarget Xanthine Oxidase Inhibitors for Therapeutic Hyperuricemia Using Virtual Screening, Network Pharmacology and in vitro Experimental Verification

Abstract In this research, based on an important target xanthine dehydrogenase/oxidase (XDH/XO) of therapeutical hyperuricemia, natural multitarget XO inhibitors are discovered from Chinese herbal medicine . As a result, 31 natural active compounds are found using network pharmacology, molecular docking and dynamic simulation computational approaches. Further experimental verification shows that hesperetin, notopterol and cnidimol B are the promising lead compounds as multitarget XO inhibitors. Moreover, hesperetin, as an obvious competitive inhibitor, has the best bioactivities (IC 50 =13.63±0.12 μM). Additionally, inhibitory mechanism illustrates that these compounds treat hyperuricemia through targets HPRT1, NT5E, XDH, HSP90AA1, STAT3, ESRI, PPARG, MAPK1, MAPK3 SIRT1, mTOR and TLR4. Relevant signaling pathways involve in SCF‐Kit signaling pathway, interleukin signaling pathway, immune system, PDGFR signaling pathway in disease, and cellular response to heat stress. Therefore, the current research provides a new idea for discovery and development of novel XOIs, and has innovative significance for the expansion of related drug research.