Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery.
Nordqvist A, Nilsson MT, Röttger S, Odell LR, Krajewski WW, Evalena Andersson C, Larhed M, Mowbray SL, Karlén A.
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.