Structural Chemistry

, Volume 30, Issue 6, pp 2123–2133 | Cite as

Structure-based virtual screening to identify inhibitors against Staphylococcus aureus MurD enzyme

  • Mohammed Afzal AzamEmail author
  • Srikanth Jupudi
Original Research


The MurD enzyme of Staphylococcus aureus is an attractive drug target as it is essential and ubiquitous in bacteria but absent in mammalian cells. In the present study, we performed in silico high-throughput virtual screening with small molecule library of 1.60 million compounds to identify potential hits. We used S. aureus modeled MurD protein for this purpose and to find the best leads, dock complexes were further subjected to the extra-precision docking and binding free energy calculations by MM-GBSA approach. It is evident that van der Waals and Coulomb energy terms are major favorable contributors while electrostatic solvation energy term strongly disfavors the binding of ligands to the S. aureus MurD enzyme. The inhibitory activity of two selected virtual hits H5 and H10 was performed against S. aureus MurD enzyme using malachite green assay. In in vitro antibacterial screening, compound H5 inhibited the growth of S. aureus NCIM 5021, S. aureus NCIM 5022, and methicillin-resistant S. aureus (MRSA strain 43300) at high concentrations while the other tested compound H10 was inactive against all the tested strains. In order to validate the stability of inhibitor-protein complex, compound H5 with the highest inhibitory against S. aureus MurD and lowest binding free energy was subjected to 30-ns molecular dynamics simulation. Further, ADMET predictions showed the favorable pharmacokinetic profile of compounds H5 and H10.


MurD enzyme Staphylococcus aureus HTVS MD simulation ADMET predictions 



2,6-diaminopimelic acid


d-glutamic acid


UDP-N-acetylmuramate:l-Ala ligase


methicillin-resistant Staphylococcus aureus


minimum inhibitory concentration


minimum bactericidal concentration


UDP-N-acetylmuramoyl-l-Ala:d-Glu ligase


UDP-N-acetylmuramoyl-l-Ala-d-Glu:meso-DAP ligase


UDPN-acetylmuramoyl-l-Ala-g-d-Glu-meso-DAP (or l-Lys):d-Ala-d-Ala ligase


N-acetylmuramic acid




root mean square deviation






Funding information

We would like to thank the Science and Engineering Research Board (SERB), Government of India, for the financial support (No. EMR/2016/002981).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11224_2019_1330_MOESM1_ESM.docx (3.3 mb)
ESM 1 (DOCX 3382 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryJSS College of PharmacyOotyIndia

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