Ligand-based pharmacophore modelling, virtual screening and docking studies to identify potential compounds against FtsZ of Mycobacterium tuberculosis

Abstract

Background and introduction: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) which is the most common cause of death from bacterial illness. Millions of victims of TB infections have been recorded including 20,800 deaths amongst HIV positive individuals. Hence, there is a rising need for new and active compounds against M. tb protein targets especially as there is a persistent resistance to the current drug treatment regime.

Aim: This study identifies new potential compounds against the M. tb target protein ftsZ via pharmacophore modelling, QSAR analysis and docking studies.

Method: Inhibitors with known PIC₅₀ were used as a training set and the pharmacophore features (1 aromatic center, 2 hydrophobic, 2 hydrogen bond acceptors and 1 hydrogen bond donor) were validated against four test set compounds. The identified hits were subjected to rigorous ADMET properties and docked using PyRx. DS visualizer was used in binding interactions study. Stability was measured based on the total number of interactions and preference given to the number of hydrogen bond interactions.

Results: Based on the number of interactions, hydrogen bonds, extensive virtual screening and ADMET filtration, 40 compounds have been identified as potential inhibitors of ftsZ with only 3 considered to be the best leads.

Significance of research: The identified compounds have potential of being drug candidate against Mycobacterium tuberculosis and may possess a novel mechanistic route in inhibiting the resistant strains.

Keywords: Docking; Filamentous temperature-sensitive protein Z (FtsZ); Mycobacterium tuberculosis (M.tb); Pharmacophore; QSAR.