TY - JOUR
T1 - Structure-based redesign of an edema toxin inhibitor
AU - Chen, Deliang
AU - Ma, Lili
AU - Kanalas, John J.
AU - Gao, Jian
AU - Pawlik, Jennifer
AU - Jimenez, Maria Estrella
AU - Walter, Mary A.
AU - Peterson, Johnny
AU - Gilbertson, Scott R.
AU - Schein, Catherine H.
N1 - Funding Information:
Support for this project was from NIAID grant U01AI5385802, and from Mission Pharmacal, San Antonio TX., and in part by grant 1UL1RR029876-01 from the National Center for Research Resources, NIH to the Institute for Translational Studies of the UTMB, (to CHS for pilot #809). The computational facilities of the Sealy Center for Molecular Biophysics and Structural Biology were used for this project.
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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 15 μg/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.
AB - 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 15 μg/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.
KW - Adenylyl cyclase toxin inhibitor
KW - Anthrax
KW - Cell-based assay
KW - Computer aided design
KW - ETEC (enterotoxigenic E. coli)
KW - Non-nucleotide inhibitors
KW - Toxicity profiling
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U2 - 10.1016/j.bmc.2011.10.091
DO - 10.1016/j.bmc.2011.10.091
M3 - Article
C2 - 22154558
AN - SCOPUS:84855196872
SN - 0968-0896
VL - 20
SP - 368
EP - 376
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 1
ER -