Fragment-Based Dynamic Combinatorial Chemistry for Identification of Selective ?-Glucosidase Inhibitors

被引：0

作者：

Wu, Yao ^{[1
]}

Liu, Changming ^{[1
]}

Hu, Lei ^{[1
]}

机构：

[1] Jiangsu Univ, Sch Pharm, Zhenjiang 212013, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2022年 / 13卷 / 11期

基金：

中国博士后科学基金;

关键词：

Dynamic combinatorial chemistry; -Glucosidase; -Amylase; Fragment-based drug design; Protein inhibition; Binding mechanism; ALPHA-GLUCOSIDASE; BIOLOGICAL EVALUATION; DUAL INHIBITORS; DRUG DISCOVERY; IN-VITRO; DERIVATIVES; LIBRARIES; AMYLASE; DESIGN;

D O I：

10.1021/acsmedchemlett.2c004051791

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Efforts to combine advantages of fragment-based drug design (FBDD) and dynamic combinatorial chemistry (DCC) for the development of selective alpha-glucosidase inhibitors were described. Starting from 5 rationally designed fragments, two iterative dynamic combinatorial libraries (DCLs) comprising 29 acylhydrazone products were generated and screened using alpha-glucosidase and alpha- amylase as the templates. The optimal ligand identified showed substantial alpha- glucosidase inhibition with high selectivity over alpha-amylase as well as low cytotoxicity. Furthermore, inhibition type and detailed ligand/enzyme binding interactions were elucidated by the binding kinetic study and docking simulation, respectively.

引用

页码：1791 / 1796

页数：6

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