| Summary: | Tuberculosis, caused by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in <i>M. tuberculosis</i> broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of <i>M. tuberculosis</i> has provided an opportunity to explore the pangenome of the species along with the pan-phylogeny and to identify potential novel drug targets leading to drug discovery. We attempt to calculate the pangenome of <i>M. tuberculosis</i> that comprises a total of 150 complete genomes and performed the phylo-genomic classification and analysis. Further, the conserved core genome (1251 proteins) is subjected to various sequential filters (non-human homology, essentiality, virulence, physicochemical parameters, and pathway analysis) resulted in identification of eight putative broad-spectrum drug targets. Upon molecular docking analyses of these targets with ligands available at the DrugBank database shortlisted a total of five promising ligands with projected inhibitory potential; namely, 2′deoxy-thymidine-5′-diphospho-alpha-<span style="font-variant: small-caps;">d</span>-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-<span style="font-variant: small-caps;">l</span>-rhamnose, thymidine-5′-triphosphate, and citicoline. We are confident that with further lead optimization and experimental validation, these lead compounds may provide a sound basis to develop safe and effective drugs against tuberculosis disease in humans.
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