Study on drug-target binding kinetics profiles of flavonoids in Chrysanthemum morifolium and xanthine oxidase.
10.19540/j.cnki.cjcmm.20201230.501
- Author:
Xue-Yan LI
1
;
Yang LIU
1
;
Fang LIU
1
;
Hong-Jiao CHEN
1
;
Wen-Ning YANG
1
;
Hai-Yang YANG
1
;
Xiao-Quan JIANG
1
;
Mu-Li SEN
1
;
Guo-Peng WANG
2
;
Jing WANG
3
;
Yan-Li PAN
4
Author Information
1. School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China.
2. Zhongcai Health(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.
4. Institute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences Beijing 100700, China.
- Publication Type:Journal Article
- Keywords:
drug-target binding kinetics;
surface plasmon resonance;
target occupancy mathematical model;
xanthine oxidase
- MeSH:
Chromatography, Liquid;
Chrysanthemum;
Flavonoids;
Kinetics;
Pharmaceutical Preparations;
Tandem Mass Spectrometry;
Xanthine Oxidase/metabolism*
- From:
China Journal of Chinese Materia Medica
2021;46(7):1822-1831
- CountryChina
- Language:Chinese
-
Abstract:
Based on the target occupancy mathematical model, the binding kinetic process of potential active ingredients of lowering uric acid in Chrysanthemum morifolium with xanthine oxidase(XOD) was evaluated. The potential active ingredients of lowering uric acid in Ch. morifolium were screened by UPLC-Q-Exactivems MS technology, reference substance identification and in vitro enzymatic kinetics experiments. The binding kinetic parameters of xanthine oxidase and potential inhibitor in Ch. morifolium were determined by surface plasma resonance(SPR). The verified mathematical model of the XOD target occupancy evaluated the kinetic binding process of inhibitors and xanthine oxidase in vivo. According to UPLC-Q-Exactive MS and reference substance identification, 39 potential uric acid-lowering active ingredients in Ch. morifolium extracts were identified and the inhibitory activities of 23 compounds were determined. Three potential xanthine oxidase inhibitors were screened, namely genistein, luteolin, and apigenin. whose IC_(50 )were 1.23, 1.47 and 1.59 μmol·L~(-1), respectively. And the binding rate constants(K_(on)) were 1.26×10~6, 5.23×10~5 and 6.36×10~5 mol·L~(-1)·s~(-1), respectively. The dissociation rate constants(K_(off)) were 10.93×10~(-2), 1.59×10~(-2), and 5.3×10~(-2 )s~(-1), respectively. After evaluation by different administration methods, the three selected compounds can perform rapid and sustained inhibition of xanthine oxidase in vivo under combined administration. This study comprehensively evaluated the target occupancy process of three effective components in different ways of administration in vivo by UPLC-MS, concentration-response method, SPR technology and xanthine oxidase target occupancy model, which would provide a new research idea and method for screening active ingredients in traditional Chinese medicine.
