Abstract

A combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S, 5R)-2,6-diamino-5-hydroxyhexanoic acid ( 4, IC(50) of 610 +/- 15 mu M). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29 were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase. (C) 2008 Elsevier Ltd. All rights reserved.

Keywords

virtual screening; glutamine synthetase; gamma-glutamyl : ammonia ligase

Published in

Bioorganic and Medicinal Chemistry
2008, volume: 16, number: 10, pages: 5501-5513

Authors' information