Discovery Of A Novel XO Inhibitor Through Molecular Docking-Based Virtual Screening And Molecular Dynamics Simulation Studies

Gout is a crystal-related arthropathy caused by congenital disorders of purine metabolism or uric acid excretion,resulting in increased blood uric acid and deposition of monosodium urate.Xanthine oxidase(XO)is the key enzyme that catalyses the metabolism of hypoxanthine and xanthine to produce uric acid in human body.Excessive content and activity in human body will produce a large amount of uric acid,and then cause gout.XO inhibitors reduce uric acid production by inhibiting XO activity in vivo.As a typical XO inhibitor,allopurinol is one of the most effective drugs for the clinical treatment of hyperuricemia and gout at present.However,allopurinol has hepatotoxicity and can induce a variety of adverse reactions.Therefore,it is of practical significance to search for natural,high safety and small toxic side effects of XO inhibitor.The study drew the following conclusions.1.allopurinol functioned as lead compounds.513 compounds similar to allopurinol were got.And the high-throughput virtual screening was performed to find an excellent inhibitor to XO.Compound named pubchem135910081(UNK)with the lowest docking energy was chosen for further study.2.Compared with allopurinol,the pharmacokinetic parameters of pubchem135910081(UNK)were predicted by ADMET on admet SAR and Swiss ADME online.In the aspect of lipophilicity,UNK is better than allopurinol;In the aspect of water solubility,both of them are above medium,and their solubility is higher;In the aspect of pharmacokinetics,allopurinol metabolizes fast in vivo,UNK metabolizes slowly,and its efficacy lasts for a long time,which is useful to reducing the frequency of taking medicine,and both of them do not pass the blood-brain barrier;In the aspect of drug like properties,the score of bioavailabilityof them is high,which proves to be a potential drug;In the aspect of drug toxicity,none of them is carcinogenic;allopurinol has mutagenicity,but unk does not;acute oral toxicity grade is grade III,which is considered safe with bee venom and without fish toxicity;Allopurinol has eye irritation,while UNK does not.All the results listed above indicted that UNK may be a potential excellent XO inhibitor.3.Molecular dynamics simulation was carried out through GROMACS 2018(software).The results showed that UNK was more stable in binding with xanthine oxidase than allopurinol.Our theoretical studies provide reliable clues for the design of better XO inhibitors.