In silico Drug Target Discovery Through Proteome Mining from M. tuberculosis: An Insight towards Antivirulent Therapy

AIM AND OBJECTIVE: One of the challenges to conventional therapies against Mycobacterium tuberculosis is the development of multi-drug resistant pathogenic strains. This study was undertaken to explore new therapeutic targets for the revolutionary antivirulence therapy utilizing the pathogen's essential hypothetical proteins, serving as virulence factors, the essential first step in novel drug designing. METHODS: Functional annotations of essential hypothetical proteins from Mycobacterium tuberculosis (H37Rv strain) were performed through domain annotation, Gene Ontology analysis, physicochemical characterization and prediction of subcellular localizations. Virulence factors among the essential hypothetical proteins were predicted, among which pathogen-specific drug target candidates, non-homologous to human and gut microbiota were identified. This was followed by druggability and spectrum analysis of the identified targets. RESULTS AND CONCLUSION: The study successfully assigned functions of 83 essential hypothetical proteins of Mycobacterium tuberculosis, among which 25 were identified as virulence factors. Out of 25, 12 virulence factors were observed as potential pathogen-specific drug target candidates. Nine potential targets had druggable properties and rest three were considered as novel targets. Exploration of these targets provided new insights to future drug development. Characterization of subcellular localizations revealed most of the predicted targets were cytoplasmic that could be ideal for intracellular drugs, while two drug targets were membrane-bound, ideal for vaccines. Spectrum analysis identified one broad spectrum and 11 narrow spectrum targets. This study would, therefore, instigate in designing novel therapeutics for antivirulence therapy, which has the potential to bring revolutionary treatment over conventional antibiotic therapies to overcome the lethality of antibiotic-resistant strains.