Rapid screening and in vivo target occupancy quantitative evaluation of xanthine oxidase inhibitors based on drug-target binding kinetics research strategy: A case study of Chrysanthemum morifolium Ramat.

被引：0

作者：

Li, Xueyan ^{[1
]}

Yang, Wenning

Chen, Hongjiao ^{[1
]}

Pan, Fulu

Liu, Wei ^{[1
]}

Qi, Dongying ^{[1
]}

Yu, Shuang

Liu, Huining ^{[1
]}

Chai, Xiaoyu ^{[1
]}

Liu, Yang ^{[1
,4
]}

Pan, Yanli ^{[2
,5
]}

Wang, Guopeng ^{[3
,6
]}

机构：

[1] Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing 102488, Peoples R China

[2] China Acad Chinese Med Sci, Inst Informat Tradit Chinese Med, Beijing 100700, Peoples R China

[3] Zhongcai Hlth Beijing Biol Technol Dev Co Ltd, Beijing 101500, Peoples R China

[4] Beijing Univ Chinese Med, Sch Chinese Mat Med, Sunshine South St, Beijing 102488, Peoples R China

[5] China Acad Chinese Med Sci, Inst Informat Tradit Chinese Med, 16 Nanxiaojie, Beijing 100700, Peoples R China

[6] Zhongcai Hlth Beijing Biol Technol Dev Co Ltd, Xingsheng South Rd, Beijing 101500, Peoples R China

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2023年 / 161卷

关键词：

Surface plasmon resonance; Chrysanthemum morifolium Ramat; Xanthine oxidase; Target occupancy; Mathematical model; RESIDENCE TIME; URIC-ACID; IDENTIFICATION; FRAGMENTATION; ASSOCIATION;

D O I：

10.1016/j.biopha.2023.114379

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Chrysanthemum morifolium Ramat. is a kind of food and drug dual-use traditional Chinese medicine possessing multiple pharmacological and biochemical benefits. In our study, a rapid and high-throughput method based on Surface plasmon resonance (SPR) biosensor technology was developed and verified for screening potential xanthine oxidase (XOD) inhibitors exemplarily in the Chrysanthemum morifolium Ramat. Coupled with ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS), 14 XODbinders were identified. In the SPR-based biosensor and molecular docking analysis, most compounds exhibited a strong affinity and binding kinetic property (association rate constant, Kon and dissociation rate constant, Koff) for XOD and could be regarded as potential inhibitors. More importantly, to further accurately assess target occupancy of candidate compounds in vivo, a mathematical model was established and verified involving three crucial intrinsic kinetic processes (Pharmacokinetics, Binding kinetic and Target kinetic). Overall, the proposed screening and assessment strategy could be proved an effective theoretical basis for further pharmacodynamic evaluation.

引用

页数：10