Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50value of 16 and 0.5 μM respectively.
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Marko
M
Jukič
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Janez
J
Ilaš
National Institute of Chemistry, Laboratory for Biocomputing and Bioinformatics, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia.
Matjaž
M
Brvar
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Danijel
D
Kikelj
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Jožko
J
Cesar
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: marko.anderluh@ffa.uni-lj.si.
Marko
M
Anderluh
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D027081:DNA Gyrase / Q000378:metabolism*; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008958:Models, Molecular; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D027081:DNA Gyrase
ATP binding site; Antibacterials; Antibiotics; DNA gyrase B; Inhibitor; Ligand-based drug design; Pyrrole-2-carboxamides; Structure-based drug design