Journal of Computer-Aided Molecular Design

, Volume 29, Issue 6, pp 541–560 | Cite as

Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC–MurF): experimental and computational characterization

  • Andrej PerdihEmail author
  • Martina Hrast
  • Kaja Pureber
  • Hélène Barreteau
  • Simona Golič Grdadolnik
  • Darko Kocjan
  • Stanislav Gobec
  • Tom Solmajer
  • Gerhard Wolber


Bacterial resistance to the available antibiotic agents underlines an urgent need for the discovery of novel antibacterial agents. Members of the bacterial Mur ligase family MurC–MurF involved in the intracellular stages of the bacterial peptidoglycan biosynthesis have recently emerged as a collection of attractive targets for novel antibacterial drug design. In this study, we have first extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing a multiple MurC–MurF ligase inhibition for representatives of the extended series of this class. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge, compound 1 represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC–MurF). Subsequent molecular dynamic (MD) simulations coupled with interaction energy calculations were performed for two alternative in silico models of compound 1 in the UMA/d-Glu- and ATP-binding sites of MurD, identifying binding in the ATP-binding site as energetically more favorable in comparison to the UMA/d-Glu-binding site, which was in agreement with steady-state kinetic data. In the final stage, based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives 811, exhibiting multiple Mur ligase (MurC–MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for compound 10 it was shown to possess promising antibacterial activity against S. aureus. These compounds represent novel leads that could by further optimization pave the way to novel antibacterial agents.


Bacterial Mur (MurC–MurF) ligase ATP-competitive inhibition Molecular dynamics (MD) Steady-state kinetics measurements Antibacterial agents Drug design 



Electrostatic potential


Generalized AMBER Force Field


Linear interaction energy method


Local reaction field


Minimum inhibitory concentration


Residual activity


Root-mean square distance


Structure–activity relationship


Surface constraint all atoms solvent








Uridine-5′-diphosphate-N-acetylmuramoyl-l-alanyl-d-glutamayl-2,6-diaminopimelic acid



This work was supported by the Ministry of Higher Education, Science and Technology of the Republic of Slovenia Postdoctoral grant number: Z1-4111. The authors would like thank Dr. Jernej Zidar from the Institute of High Performance Computing (IHPC), Singapure and Barbara Pogorelčnik from the National institute of Chemistry, Slovenia, for their technical assistance with MD calculations. Dr. Sandy Favini, Dr. Carlos Contreras-Martel and Dr. Andréa Dessen from the Bacterial Pathogenicity Group at L’Institut de Biologie Structurale (IBS), Grenoble, France are acknowledged and thanked for performing several initial structural experiments on MurD, MurE and MurF enzymes. Dr. Andreja Kovač from the Faculty of Pharmacy, University of Ljubljana is acknowledged for performing initial inhibition assays of some of the novel compounds discussed in this work. Dr. Katja Kristan from Lek Pharmaceuticals is thanked for useful discussions concerning the steady-state kinetics measurements. We are grateful to Dr. Didier Blanot from the Université Paris-Sud, Orsay, France for critical reading of the manuscript.

Supplementary material

Supplementary material 1 (MPG 61967 kb)

Supplementary material 2 (MPG 59716 kb)

10822_2015_9843_MOESM3_ESM.pdf (1 mb)
Supplementary material 3 (PDF 1028 kb)


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Andrej Perdih
    • 1
    • 2
    Email author
  • Martina Hrast
    • 3
  • Kaja Pureber
    • 1
    • 4
  • Hélène Barreteau
    • 5
  • Simona Golič Grdadolnik
    • 1
    • 4
  • Darko Kocjan
    • 1
    • 4
  • Stanislav Gobec
    • 3
  • Tom Solmajer
    • 1
  • Gerhard Wolber
    • 2
  1. 1.National Institute of ChemistryLjubljanaSlovenia
  2. 2.Institute of PharmacyFreie Universität BerlinBerlinGermany
  3. 3.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  4. 4.EN-FIST Centre of ExcellenceLjubljanaSlovenia
  5. 5.Laboratoire des Enveloppes Bactériennes et Antibiotiques, IBBMCUniversité Paris-SudOrsayFrance

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