Simulation Analysis of Occupancy Rates of Baicalein， Quercetin and Galangin on Target Sites of Xanthine Oxidase
10.13422/j.cnki.syfjx.20210485
- VernacularTitle:黄芩素、槲皮素、高良姜素对黄嘌呤氧化酶靶点占有率的模拟分析
- Author:
Hai-yang YANG
1
;
Guo-peng WANG
2
;
Wen-ning YANG
1
;
Xue-yan LI
1
;
Mu-li SEN
1
;
Xiao-quan JIANG
1
;
Jing WANG
3
;
Yang LIU
1
Author Information
1. School of Chinese Materia Medica，Beijing University of Chinese Medicine，Beijing 102488， China
2. Zhongcai Hanxi （Beijing） Biological Technology Development Co. Ltd.，Beijing 101503， China
3. State Key Laboratory of Natural and Biomimetic Drugs，School of Pharmaceutical Sciences， Peking University，Beijing 100191，China
- Publication Type:Research Article
- Keywords:
xanthine oxidase;
target occupancy;
drug target binding kinetics;
association rate constant （kon）;
dissociation rate constant （koff）;
half inhibitory concentration （IC50）;
surface plasmon resonance （SPR）
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2021;27(14):147-154
- CountryChina
- Language:Chinese
-
Abstract:
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 （IC50） 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 （kon） and dissociation rate constant （koff） 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 IC50 values of febuxostat， baicalein， quercetin and galangin were 0.002 7， 1.63， 0.38， 1.59 µmol·L-1， respectively. The IC50 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 of 100 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.
