摘要
目的:模拟分析黄芩素、槲皮素、高良姜素对黄嘌呤氧化酶体内靶点占有率。方法:通过体外酶促反应测定非布司他、黄芩素、槲皮素、高良姜素对黄嘌呤氧化酶的半数抑制浓度(IC_(50)),利用分子对接技术对其结合自由能进行预测,同时,采用表面等离子共振技术测定其结合速率常数(k_(on))和解离速率常数(k_(off))。基于测定的结合动力学参数和提取的药物代谢动力学数据建立体内靶点占有率模型。结果:非布司他、黄芩素、槲皮素、高良姜素对黄嘌呤氧化酶的IC_(50)分别为0.0027,1.63,0.38,1.59μmol·L^(-1),非布司他的IC_(50)与文献报道一致。预测的非布司他体内靶点占有率曲线与其临床药效持续时间相吻合。当大鼠按100 mg·kg^(-1)单次灌胃给予槲皮素长循环脂质体时,体内靶点占有率>70%的持续时间约3.9 h;当大鼠按200 mg·kg^(-1)单次口服给予黄芩素和高良姜素时,体内靶点占有率>50%的持续时间分别约为10,1.7 h。结论:利用药靶结合动力学和体内药代动力学曲线建立的黄嘌呤氧化酶靶点占有率预测模型能有效地评估化合物对靶点的体内抑制活性。
Objective:To simulate the occupancy rates of baicalein,quercetin and galangin on the target sites of xanthine oxidase in vivo.Method:In this experiment,the half inhibitory concentration(IC_(50))of febuxostat,baicalein,quercetin and galangin against xanthine oxidase were determined by in vitro enzymatic reaction.Binding free energy was predicted by molecular docking technology and their association rate constant(k_(on))and dissociation rate constant(k_(off))were determined by surface plasmon resonance technology.Based on measured binding kinetic parameters(kon and koff)and extracted pharmacokinetic data,the target occupancy model in vivo was established.Result:The IC_(50)values of febuxostat,baicalein,quercetin and galangin were0.0027,1.63,0.38,1.59μmol·L^(-1),respectively.The IC_(50)of febuxostat was very close to that reported in the literature.The predicted curve of target occupancy rate in vivo of febuxostat was consistent with its duration of clinical efficacy.When single intragastric administration of long-circulating liposomes of quercetin with dose of100 mg·kg^(-1)in rats,the time of target occupancy rate>70%in vivo lasted for about 3.9 h.When rats were orally administered baicalein and galangin with dose of 200 mg·kg^(-1),the time of target occupancy rate>50%in vivo lasted for about 10 h and 1.7 h,respectively.Conclusion:The prediction model of xanthine oxidase target occupancy constructed by drug target binding kinetics and in vivo pharmacokinetic curves can effectively evaluate the in vivo inhibitory activity of compounds against the target.
作者
杨海洋
汪国鹏
杨文宁
李雪岩
森慕黎
江晓泉
王静
刘洋
YANG Hai-yang;WANG Guo-peng;YANG Wen-ning;LI Xue-yan;SEN Mu-li;JIANG Xiao-quan;WANG Jing;LIU Yang(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488,China;Zhongcai Hanxi(Beijing)Biological Technology Development Co.Ltd.,Beijing 101503,China;State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China)
出处
《中国实验方剂学杂志》
CAS
CSCD
北大核心
2021年第14期147-154,共8页
Chinese Journal of Experimental Traditional Medical Formulae
基金
国家自然科学基金项目(81973295)。
