A novel pharmacophore model for the design of anthrax lethal factor inhibitors.
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.
Yuan
Hongbin
H
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Johnson
Sherida L
SL
Chen
Li-Hsing
LH
Wei
Jun
J
Pellecchia
Maurizio
M
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
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; C030325:anthrax toxin; D045726:Metalloproteases