Fragment based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor.

Title

Fragment based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor.

Creator

Shin WS; Nguyen ME; Bergstrom A; Jennings IR; Crowder MW; Muthyala R; Sham YY

Publisher

Chemical Biology & Drug Design

Date

2021
2021-06-20

Description

Metallo-β–lactamases (MBLs) are zinc-containing carbapenemases that inactivate a broad range of β–lactam antibiotics. There is a lack of β–lactamase inhibitors for restoring existing β–lactam antibiotics arsenals against common bacterial infections. Fragment-based screening of a non-specific metal chelator library demonstrates 8-hydroxyquinoline as a broad-spectrum nanomolar inhibitor against VIM-2 and NDM-1. A hit-based substructure search provided an early structure–activity relationship of 8-hydroxyquinolines and identified 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic β–lactamase inhibitor that can restore β–lactam activity against VIM-2-expressing E. coli. Molecular modeling further shed structural insight into its potential mode of binding within the dinuclear zinc active site. 8-Hydroxyquinoline-7-carboxylic acid is highly stable in human plasma and human liver microsomal study, making it an ideal lead candidate for further development.

NEOMED College

NEOMED College of Medicine

NEOMED Department

Department of Pharmaceutical Sciences

Update Year & Number

Jan to Aug list 2021

Citation

Shin WS; Nguyen ME; Bergstrom A; Jennings IR; Crowder MW; Muthyala R; Sham YY, “Fragment based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor.,” NEOMED Bibliography Database, accessed May 28, 2024, https://neomed.omeka.net/items/show/11847.