Thioamide hydroxypyrothiones supersede amide hydroxypyrothiones in potency against anthrax lethal factor.
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.
Agrawal
Arpita
A
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
de Oliveira
César Augusto F
CA
Cheng
Yuhui
Y
Jacobsen
Jennifer A
JA
McCammon
J Andrew
JA
Cohen
Seth M
SM
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
D000577:Amides; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008024:Ligands; D013854:Thioamides; D013871:Thiones; C030325:anthrax toxin