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Bioorg Med Chem. 2008 May 15;16(10):5501-13. doi: 10.1016/j.bmc.2008.04.015. Epub 2008 Apr 11.

Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery.

Author information

1
Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-751 23 Uppsala, Sweden.

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+/-15microM). 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.

PMID:
18462943
DOI:
10.1016/j.bmc.2008.04.015
[Indexed for MEDLINE]

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