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

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 (2 S,5 R)-2,6-diamino-5-hydroxyhexanoic acid ( 4, IC 50 of 610 ± 15 μM). 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.