Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations

Abstract

Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r²_ncv and r²_loo values. The predictive ability of these models was determined and an acceptable predictive correlation (r²_Pred) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors.

Graphical Abstract

Keywords:

• CoMFA
• CoMSIA
• PLS
• FtsZ
• XP
• MD

Acknowledgements

We greatly acknowledge Tripos Inc, USA and Schrödinger LLC, New York for providing the software. We wish to express our gratitude to Department of Chemistry, Osmania University for providing facilities to carry out the research work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was made possible through grants from DST – Science and Engineering Research Board [SB/EMEQ-004/2013], Council of Scientific and Industrial Research [01/(2436)/10/EMR-II] and University Grants Commission [42–233/2013(SR)], New Delhi, India. The authors SB and RI would like to acknowledge financial support from University Grants Commission for research fellowships.