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

Anneli Nordqvist, Mikael T Nilsson, Svenja Röttger, Luke R Odell, Wojciech W Krajewski, C Evalena Andersson, Mats Larhed, Sherry L Mowbray, Anders Karlén

Index: Bioorg. Med. Chem. 16 , 5501-13, (2008)

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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.