Molecular dynamics analysis of the effects of GTP, GDP and benzimidazole derivative on structural dynamics of a cell division protein FtsZ from Mycobacterium tuberculosis

Abstract

The prevailing multi-drug resistance in Mycobacterium tuberculosis continues to remain one of the main challenges to combat tuberculosis. Hence, it becomes imperative to focus on novel drug targets. Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein, a eukaryotic tubulin homologue and a promising drug target. During cytokinesis, FtsZ polymerises in the presence of GTP to form Z-ring and recruits other proteins at this site that eventually lead to the formation of daughter cells. Benzimidazoles were experimentally shown to inhibit Mtb-FtsZ, with one of the benzimidazole derivatives, M1, being reported to have the minimum inhibitory concentration (MIC) value of 3.13 µg/mL. In the present study, mechanism of destabilisation of FtsZ in the presence of M1 was computationally investigated in the presence of its substrate GTP/GDP employing molecular dynamics (MD) simulation analysis, principal component analysis (PCA), molecular mechanics combined with the generalised Born and surface area continuum salvation (MM-GBSA) and density functional theory (DFT). From the analyses, it is proposed that binding of M1 in the inter-domain cleft induces structural changes in the GTP-binding region that affect GTP binding, thus switching the preference of this protein towards depolymerised state and eventually inhibiting the cell division. Hence, this study provides mechanistic insights into the design of novel benzimidazole inhibitors against Mtb-FtsZ.

Communicated by Ramaswamy H. Sarma

Keywords:

• Mtb-FtsZ
• benzimidazole (M1)
• GTP/GDP
• molecular dynamics simulations
• MM-GBSA
• PCA

Acknowledgements

Department of Biotechnology, Govt. of India, is acknowledged for sponsoring Bioinformatics Infrastructure Facility (BIF) at the School of Biotechnology, Shri Mata Vaishno Devi University (SMVDU). The authors are thankful to Dr. Ding Li at the College of Chemistry & Pharmacy Northwest A&F University Yangling 712100, China, for providing the docked complex of inhibitor (M1) and Mtb-FtsZ. The intellectual support of Prof. M.V. Deshpande, Emeritus Scientist CSIR-National Chemical Laboratory (NCL), Pune, India, and Dr. K. Kulkarni, Senior Scientist, CSIR-NCL Pune, India, is highly acknowledged. The authors would like to thank Department of Pharmacy, Central University of Rajasthan, for providing access to Schrodinger Prime & Glide tools. The authors appreciate Varun Sharma, Research Scholar, Human Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, for his resourceful suggestions.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author Contributions

SH, IS and RC conceived the plan of the study. SH and IS carried out and analysed the MD simulations. VNU performed the protein intrinsic disorder propensity. AU and YK assisted in carrying out the DFT calculations. VV contributed in continuous implementation of the work. Manuscript drafting was equally shared by all the authors.