Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), 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 M. tuberculosis broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of M. tuberculosis 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 M. tuberculosis 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-d-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-l-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.
Highlights
According to the 2019 global World Health Organization (WHO) report, tuberculosis (TB)is among the top ten causes of death and the leading cause of a single infectious agent [1]
The increased occurrence of multidrug resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis has been attributed to spontaneous mutations in the bacterial genome, followed by the emergence of these mutant strains at the expense of wild type strains [3]
A total of 150 complete genomes and associated proteomes of M. tuberculosis were downloaded from the National Center for Biotechnology Information (NCBI)
Summary
According to the 2019 global World Health Organization (WHO) report, tuberculosis (TB). Various protocols in bioinformatics have helped scientists to process biological data of pathogens in order to prioritize drug targets, while the parallel developments in the cheminformatics help researchers access ligand databases such as the DrugBank and perform virtual screening for in silico-aided drug discovery [7,8]. Utilizing these useful tools, scientists have endeavored to identify lead compounds for tuberculosis [9,10]. This research work will provide a sound basis for developing novel therapeutics against the most troublesome bacterial pathogen M. tuberculosis
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