title: A novel pharmacophore model for the design of anthrax lethal factor inhibitors.
abstract: This study aims at the identification of novel structural features on the surface of the Zn-dependent metalloprotease lethal factor (LF) from anthrax onto which to design novel and selective inhibitors. We report that by targeting an unexplored region of LF that exhibits ligand-induced conformational changes, we could obtain inhibitors with at least 30-fold LF selectivity compared to two other most related human metalloproteases, MMP-2 and MMP-9. Based on these results, we propose a novel pharmacophore model that, together with the preliminarily identified compounds, should help the design of more potent and selective inhibitors against anthrax.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Sherida L
authors.initials: SL
authors.lastname: Johnson
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial / Q000737:chemistry; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; C030325:anthrax toxin; D045726:Metalloproteases