title: Structure-based redesign of an edema toxin inhibitor.
abstract: Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria.
authors.affiliation: Sealy Center for Structural Biology and Molecular Biophysics, Department of Biochemistry and Molecular Biology, UTMB, Galveston, TX 77555-0857, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Chen
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
authors.forename: John J
authors.initials: JJ
authors.lastname: Kanalas
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pawlik
authors.forename: Maria Estrella
authors.initials: ME
authors.lastname: Jimenez
authors.forename: Mary A
authors.initials: MA
authors.lastname: Walter
authors.forename: Johnny W
authors.initials: JW
authors.lastname: Peterson
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gilbertson
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Schein
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001408:Bacillus anthracis / Q000378:metabolism*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D005449:Fluorenes / Q000737:chemistry; D051379:Mice; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D001565:Benzoates; D005449:Fluorenes; C030325:anthrax toxin; C041509:fluorene; D000242:Cyclic AMP; D000262:Adenylyl Cyclases