Virtual screening for potential inhibitors of bacterial MurC and MurD ligases

• Published in: Journal of molecular modeling 2012-03, Vol.18 (3), p.1063-1072
• Main Authors: Tomašić, Tihomir, Kovač, Andreja, Klebe, Gerhard, Blanot, Didier, Gobec, Stanislav, Kikelj, Danijel, Mašič, Lucija Peterlin
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate; Anti-Bacterial Agents - chemistry; Bacterial Proteins - antagonists & inhibitors; Binding, Competitive; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer Simulation; Drug Discovery - methods; Ligases - antagonists & inhibitors; Molecular Medicine; Original Paper; Peptide Synthases - antagonists & inhibitors; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-011-1139-8

Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency. Figure Structure and predicted binding mode of dual 1,3,5-triazine-based inhibitor in E. coli MurC and MurD active sites