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

ABSTRACT: Efforts to combine advantages of fragment-based drug design (FBDD) and dynamic combinatorial chemistry (DCC) for the development of selective α-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 α-glucosidase and α-amylase as the templates. The optimal ligand identified showed substantial α-glucosidase inhibition with high selectivity over α-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.

SUBMITTER: Wu Y

PROVIDER: S-EPMC9661702 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Wu Yao Y Liu Changming C Hu Lei L

ACS medicinal chemistry letters 20221019 11

Efforts to combine advantages of fragment-based drug design (FBDD) and dynamic combinatorial chemistry (DCC) for the development of selective α-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 α-glucosidase and α-amylase as the templates. The optimal ligand identified showed substantial α-glucosidase inhibition with high selectivity over ...[more]

PMID: 36385930

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