title: 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 (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.
authors.affiliation: Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anneli
authors.initials: A
authors.lastname: Nordqvist
authors.forename: Mikael T
authors.initials: MT
authors.lastname: Nilsson
authors.forename: Svenja
authors.initials: S
authors.lastname: Röttger
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Wojciech W
authors.initials: WW
authors.lastname: Krajewski
authors.forename: C
authors.initials: C
authors.lastname: Evalena Andersson
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D006901:Hydroxylysine / Q000031:analogs & derivatives; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009943:Organophosphorus Compounds; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C530724:(3-(diethoxyphosphoryl)phenylamino)acetic acid; D000596:Amino Acids; D002208:Caproates; D009943:Organophosphorus Compounds; D054852:Small Molecule Libraries; D006901:Hydroxylysine; D005974:Glutamate-Ammonia Ligase