【摘要】 采用拉伸分子动力学模拟的方法研究了黄嘌呤氧化酶(Xanthine oxidase, XO)抑制剂别嘌呤醇(Allopurinol)和葛根素(Puerarin)从XO离去通道解离的动态过程.分子对接结果表明,别嘌呤醇和葛根素均结合在XO的钼蝶呤中心(Molybdopterin, Mo-pt);丙氨酸扫描的结果显示, Val789, Arg880, Phe911, Phe914和Val1081在XO与抑制剂的结合中起到非常重要的作用.拉伸分子动力学模拟结果显示,相比于葛根素,别嘌呤醇需要更大的外力和更长的时间才能从XO中解离,拉伸过程中Arg880, Phe1009, Thr1010, Val1011和Ala1079均对维持2种复合物的结构稳定起到重要作用, Phe649和Phe1013在抑制剂解离过程中起到门控的作用, His875起到阻碍抑制剂解离的作用.更多还原

【Abstract】 At present,Xanthine Oxidase(XO)inhibitors are the main drugs used to treat gout and hyperuricemia. The interaction between XO and inhibitors is a hot study spot. The unbinding pathway of XO inhibitors(Allopurinol and Puerarin)were analysed via steered molecular dynamics simulation. Molecular docking results showed that allopurinol and puerarin were bound to the MO-pt center of XO. Alanine scanning results indicted that Val789,Arg880,Phe911,Phe914 and Val1081 played very important roles for inhibitors binding to XO. The tunnel analysis based on CAVER 3.0 illustrated the shape of the tunnel was relatively regular,which was beneficial to the dissociation of the inhibitors. The steered molecular dynamics simulation results revealed that compared to puerarin,allopurinol needed more external force and longer time to escape from XO.In addition,Phe1009,Arg880,Ala1079,Val1011 and Thr1010 all played important roles in maintaining the structural stability of the two compounds binding to XO,Phe649 and Phe1013 functioned a gating role in the process of inhibitor dissociation,and His875 played a blocking role in inhibitors dissociation. The results provided some theoretical clues for the study of the interaction between inhibitors and XO. Puerarin can be developed as a mild candidate medicine for the treatment of gout in the future.更多还原