Structure based virtual screening, molecular docking and molecular dynamics simulation of drug like small molecules against cell cycle regulator enzyme FtsZ of Mycobacterium tuberculosis

Abstract

Tuberculosis is a major public health problem in several developing and low income countries. It warranted 1.2 million deaths around the world in 2019. An active Tb patient can spread a large number of bacilli to the environment by coughing, spitting, speaking and sneezing which in turn help in development of new Tb cases. Further development of drug resistant strains of Mycobacterium tuberculosis to most powerful first line drugs viz., rifampicin and isoniazid put a hurdle in Tb elimination programme. Thus it is essential to explore new drug molecules to fight against Tb morbidity and mortality. In the present study an attempt has been made to screen new small drug like molecules using structure based molecular screening. 3D structure of cell cycle regulator enzyme FtsZ (PDB ID: 1RLU) was retrieved from the Protein Data Bank website and used it for structure-based virtual screening of drug like small molecules from PubChem database. The screened drugs were re-docked with FtsZ of M. tuberculosis to find out their affinity and antagonistic effect against M. tuberculosis. Molecular dynamics simulation studies were carried out for each of the docked complex to find out the stability and flexibility of the docked conformations. In silico ADME study was carried out to find out the drug likeliness of the selected molecules. A total of 1501 drug like small molecules were recovered through virtual screening of which three molecules, viz., Lig-24284406, Lig-49671233 and Lig-24791139 were taken for the docking study. It was observed that the selected drug molecules had a strong affinity towards the FtsZ. This was evident from the binding energy of the drug molecules towards FtsZ (-7.23, -9.67 and -5.51). The strong stability and flexibility of the docked structures were also evident from RMSD values i.e, < 2 Å and RMSF value i.e, > 1 Å for all the docking complexes. The present study suggested that three small drug like molecules could be taken for further clinical studies to find their efficacy against tuberculosis.

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