Combining molecular docking and molecular dynamics studies for modelling Staphylococcus aureus MurD inhibitory activity

ABSTRACT

The ATP-dependent bacterial MurD enzyme catalyses the formation of the peptide bond between cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine and D-glutamic acid. This is essential for bacterial cell wall peptidoglycan synthesis in both Gram-positive and Gram-negative bacteria. MurD is recognized as an important target for the development of new antibacterial agents. In the present study we prepared the 3D-stucture of the catalytic pocket of the Staphylococcus aureus MurD enzyme by homology modelling. Extra-precision docking, binding free energy calculation by the MM–GBSA approach and a 40 ns molecular dynamics (MD) simulation of 2-thioxothiazolidin-4-one based inhibitor $1 was carried out to elucidate its inhibition potential for the S. aureus MurD enzyme. Molecular docking results showed that Lys19, Gly147, Tyr148, Lys328, Thr330 and Phe431 residues are responsible for the inhibitor–protein complex stabilization. Binding free energy calculation revealed electrostatic solvation and van der Waals energy components as major contributors for the inhibitor binding. The inhibitor-modelled S. aureus protein complex had a stable conformation in response to the atomic flexibility and interaction, when subjected to MD simulation at 40 ns in aqueous solution. We designed some molecules as potent inhibitors of S. aureus MurD, and to validate the stability of the designed molecule D1-modelled protein complex we performed a 20 ns MD simulation. Results obtained from this study can be utilized for the design of potent S. aureus MurD inhibitors.

KEYWORDS:

• Staphylococcus aureus
• MurD
• extra-precision docking
• MM–GBSA
• MD simulation

Supplemental Material

Supplementary material for this article can be accessed here: https://doi.org/10.1080/1062936X.2018.1539034

Acknowledgements

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

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the Science and Engineering Research Board (SERB), Government of India [EMR/2016/002981]