title: Identification of small molecule inhibitors of anthrax lethal factor.
abstract: The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.
authors.affiliation: Developmental Therapeutics Program, NCI Frederick, Frederick, Maryland 21702-1201, USA. panchal@dtpax2.ncifcrf.gov
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.forename: Ann R
authors.initials: AR
authors.lastname: Hermone
authors.forename: Tam Luong
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Thiang Yian
authors.initials: TY
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: James
authors.initials: J
authors.lastname: Schmidt
authors.forename: Douglas
authors.initials: D
authors.lastname: Lane
authors.forename: Connor
authors.initials: C
authors.lastname: McGrath
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: James
authors.initials: J
authors.lastname: Burnett
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
authors.forename: Stephen
authors.initials: S
authors.lastname: Little
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Zaharevitz
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin