Targeting essential cell wall lipase Rv3802c for potential therapeutics against tuberculosis

Cell wall and lipid metabolism plays a vital role in the survival and infection of Mycobacterium tuberculosis. Increase in the incidences of life-threatening multidrug-resistant (MDR) and extreme drug-resistant (XDR) tuberculosis worsens the existing scenario and urge the need of new druggable targets and new drugs. Targeting Rv3802c, an essential cell wall lipase, can open up a new arsenal to fight the dreadful opportunistic pathogen. Our current study highlights the essentiality of Rv3802c. Its 3D structure is predicted for the first time which provides insight in identifying the ligand binding sites. Our analysis showed Rv3802c is highly conserved throughout mycobacterial species with no significant sequence homolog found in human proteome. Virtual screening followed by comparative docking studies of Rv3802c with its closest human structural homolog has been carried out to identify potential inhibitors effective towards mycobacterial proteins. Two diverse molecules from ZINC database, ZINC26726377 and ZINC43866786 have been identified as potential inhibitors effective towards Rv3802c based on the difference in predicted binding free energy of −3.99 and −3.28 kcal/mol respectively. Rv3802c is a promising drug target and also a step towards understanding and targeting the pathogen's cell wall and lipid metabolism simultaneously to combat tuberculosis.

Graphical abstractRv3802c participates in cell wall and lipid metabolism, identified as promising drug target to combat tuberculosis. Diverse molecules ZINC26726377 and ZINC43866786 have been identified as potential mycobacterial-specific inhibitors.Figure optionsDownload full-size imageDownload high-quality image (184 K)Download as PowerPoint slideHighlights► Enzymes from cell wall and lipid metabolism is good drug target for tuberculosis. ► Bioinformatics analysis identified Rv3802c as a promising druggable target. ► Virtual screening was employed to identify potential inhibitors. ► Comparative docking with human MGL was carried out to identify specific inhibitors. ► ZINC26726377 and ZINC43866786 identified as potential mycobacteria-specific inhibitors.