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Virtual screening for potential inhibitors of bacterial MurC and MurD ligases

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Abstract

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.

Structure and predicted binding mode of dual 1,3,5-triazine-based inhibitor in E. coli MurC and MurD active sites

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Acknowledgments

This work was supported by the Sixth Framework Programme (FP6) Integrated Project Inhibition of New TArgets for Fighting Antibiotic Resistance (EUR-INTAFAR) (Project No. LSHM-CT-2004-512138), by the Slovenian Research Agency (Grant No. P1-0208) and by the World Federation of Scientists. The authors thank Professor Roger Pain for critical reading of the manuscript.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Tihomir Tomašić, Andreja Kovač, Stanislav Gobec, Danijel Kikelj & Lucija Peterlin Mašič

  2. Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany

    Gerhard Klebe

  3. Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, Univ Paris-Sud, 91405, Orsay, France

    Didier Blanot

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  1. Tihomir Tomašić
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  2. Andreja Kovač
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Correspondence to Lucija Peterlin Mašič.

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Tomašić, T., Kovač, A., Klebe, G. et al. Virtual screening for potential inhibitors of bacterial MurC and MurD ligases. J Mol Model 18, 1063–1072 (2012). https://doi.org/10.1007/s00894-011-1139-8

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  • DOI: https://doi.org/10.1007/s00894-011-1139-8

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