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

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 (IC50=13.63 & PLUSMN;0.12 & mu;M). 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.