title: Thioamide hydroxypyrothiones supersede amide hydroxypyrothiones in potency against anthrax lethal factor.
abstract: Anthrax lethal factor (LF) is a critical virulence factor in the pathogenesis of anthrax. A structure-activity relationship (SAR) of potential lethal factor inhibitors (LFi) is presented in which the zinc-binding group (ZBG), linker, and backbone moieties for a series of hydroxypyrone-based compounds were systematically varied. It was found that hydroxypyrothione ZBGs generate more potent inhibitors than hydroxypyrone ZBGs. Furthermore, coupling the hydroxypyrothione to a backbone group via a thioamide bond improves potency when compared to an amide linker. QM/MM studies show that the thioamide bond in these inhibitors allows for the formation of two additional hydrogen bonds with the protein active site. In both types of hydroxypyrothione compounds, ligand efficiencies of 0.29-0.54 kcal mol(-1) per heavy atom were achieved. The results highlight the need for a better understanding to optimize the interplay between the ZBG, linker, and backbone to get improved LFi.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Arpita
authors.initials: A
authors.lastname: Agrawal
authors.forename: César Augusto F
authors.initials: CA
authors.lastname: de Oliveira
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Cheng
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Jacobsen
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000737:chemistry* / Q000494:pharmacology; D013871:Thiones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008024:Ligands; D013854:Thioamides; D013871:Thiones; C030325:anthrax toxin