Study On Active Compounds And Potential Multi-target Of Diazine And Coumarin Derivatives For Treating Hyperuricemia

Hyperuricemia is a metabolic disease,which is caused by hereditary or acquired purine metabolic disorder or by decreased uric acid excretion.It is closely related to the occurrence of gout,hypertension,diabetes,hyperlipidemia,cardiovascular disease,kidney disease,metabolic syndrome,and many other diseases.However,xanthine oxidase as rate-limiting enzyme for the production of uric acid,is an important target for the research and development of novel drugs.Xanthine oxidase inhibitors（XOIs）can inhibit the production of uric acid and fundamentally solve the problem of excessive uric acid.Compared to single-target drugs,multi-target drugs are not prone to adverse reactions and exert a synergistic effect.Therefore,the discovery of new multi-target XOIs and their mechanism of therapeutic hyperuricemia are important to overcome adverse effects and resistance to currently available drugs.Therefore,in order to better cure hyperuricemia,comperhensive utilization of QSAR,molecular docking,dynamics simulation,network pharmacology and in vitro assays discovers multi-target interaction anti-hyperuricemia XOIs from diazine,coumarin derivatives,and 5 coumarin-containing Chinese herbs and explores their inhibitory mechanism.The main results are as follows:（1）Six QSAR models（2 HQSAR models and 4 Co MSIA models）of XOIs diazine and coumarin derivatives for treatment of hyperuricemia have been developed to understand chemical-biological interactions.All constructed QSAR models have accurately predictive results(R²=0.893～0.998,Q²=0.536～0.875 and Q_ext²=0.883～0.949).The developed QSAR models have good robustness and external prediction ability and can provide a platform for quantitative predicted bioactivity of new drugs.（2）Mechanistic studies have identified seven genes,including xanthine dehydrogenase（XDH）,cyclin dependent kinase inhibitor 1A（CDKN1A）,MYC proto-oncogene protein（MYC）,protein tyrosine phosphatase non-receptor type 11（PTPN11）,platelet derived growth factor receptor beta（PDGFRB）,toll like receptor 4（TLR4）,and signal transducer and activator of transcription 1（STAT1）,as highly relevant targets for treatment of hyperuricemia.In addition,TANK-binding kinase 1（TBK1）,diacylglycerol O-acyltransferase 1（DGAT1）,peroxisome proliferator activated receptor delta（PPARD）,phosphodiesterase 6C（PDE6C）,eukaryotic translation initiation factor 4E（EIF4E）,component of inhibitor of nuclear factor kappa B kinase complex（CHUK）,solute carrier family 2 member 1（SLC2A1）,phosphoinositide-3-kinase regulatory subunit 1（PIK3R1）,adenosine monophosphate deaminase 3（AMPD3）,and peroxisome proliferator activated receptor gamma（PPARG）,may also be associated with the treatment of hyperuricemia.These targets are involved in biological processes such as protein phosphorylation,hypoxia stress,pain perception,and inflammatory response,and regulate multiple signaling pathways,including insulin resistance,SCF-Kit signaling pathway,interleukin signaling pathway,immune system,PDGFR signaling pathway in diseases,and cellular response to heat stress,exerting a synergistic effect in treatment of hyperuricemia.Therefore,the research results of these targets and pathways will help to explore the underlying mechanisms for treatment of hyperuricemia and provide important information and reference in related drug development.（3）Using QSAR models,molecular docking,molecular dynamics simulations,and network pharmacology methods,24 diazine derivatives,14 coumarin derivatives,and 31natural ingredients as multi-target XOIs lead compounds were obtained through virtual screening from databases（Pub Chem,ZINC,TCMID,and TCMSP）.Based on theoretical research results,8 compounds（hesperetin,notopterol,imperatorin,herbacetin,oxypeucedanin hydrate,ferulic acid and isoferulic acid）inhibition properties were investigated on XO activity.All compounds exhibited good inhibition activities.Especially,compared with positive control allopurinol,hesperetin has significant inhibition activities with IC₅₀ value 13.63±0.12μM.Additionally,notopterol showed similar inhibition activities with IC₅₀ value 24.93±0.73μM.Moreover,inhibition kinetics study indicated that hesperetin is competitive inhibitor.notopterol is uncompetitive inhibition.Therefore,the obtained compounds are worthy of further developing as multi-target XOIs for better treatment of hyperuricemia.