Computational study of the piperidine and FtsZ interaction in Salmonella Typhi: implications for disrupting cell division machinery

Abstract

FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an in-silico drug interaction study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) Salmonella Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR Salmonella Typhi.

Communicated by Ramaswamy H. Sarma

Keywords:

• Enteric fever
• multidrug resistance
• molecular docking
• simulations
• virtual screening
• structural dynamics

Acknowledgements

All authors would like to thank The CHILDS Trust Medical Research Foundation, Chennai and the management of Vellore Institute of Technology, Vellore, for providing technical facilities during the research work. The authors would also like to acknowledge Mr. Soumya Basu [ICMR-RA], Mr. Aniket Naha [ICMR-RA] and Mr. Dipjyothi Dey [KKCTH, Chennai] for their inputs in the manuscript. HK would like to thank ICMR for their research fellowships.

Author contributions

SR administered the study, acquired funding, and reviewed the manuscript. AA and AM supervised and investigated the study, acquired funding, and reviewed the manuscript. HK conceptualized data curation and contributed to formal analysis, manuscript writing and formatting.

Data availability statement

This study’s supporting datasets and analytics can be found in the article and Supplementary Material provided. The names of the repositories and identifiers can be found in the article Supplementary Material.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work has been funded by the Indian Council of Medical Research (ICMR), a Government of India agency, NewDelhi, for the research grant [IRIS ID: 2020-0690].