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

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Abstract

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.

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Abbreviations

DAP:

2,6-diaminopimelic acid

d-Glu:

d-glutamic acid

MurC:

UDP-N-acetylmuramate:l-Ala ligase

MRSA:

methicillin-resistant Staphylococcus aureus

MIC:

minimum inhibitory concentration

MBC:

minimum bactericidal concentration

MurD:

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

MurE:

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

MurF:

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

MurNAc:

N-acetylmuramic acid

UDP:

uridine-5′-diphosphate

RMSD:

root mean square deviation

UMA:

uridine-5′-diphosphate-N-acetylmueamoyl-l-alanine

UMAG:

UDP-N-acetylmuramoyl-l-alanine-d-glutamat

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Funding

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

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  1. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India

    Mohammed Afzal Azam & Srikanth Jupudi

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  1. Mohammed Afzal Azam
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Correspondence to Mohammed Afzal Azam.

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Azam, M.A., Jupudi, S. Structure-based virtual screening to identify inhibitors against Staphylococcus aureus MurD enzyme. Struct Chem 30, 2123–2133 (2019). https://doi.org/10.1007/s11224-019-01330-z

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