Integrated Virtual Screening and MD Simulation Study to Discover Potential Inhibitors of Mycobacterial Electron Transfer Flavoprotein-Oxidoreductase

Abstract

Tuberculosis (TB) remains a global health crisis, contributing significantly to both morbidity and mortality. The escalating resistance to existing drugs exacerbates the urgency for innovative therapeutic strategies. This study focuses on repurposing drugs against the crucial mycobacterial protein, electron transfer flavoprotein oxidoreductase (EtfD), integral to utilizing fatty acids and cholesterol as a carbon source during infection. The research adopted an integrative approach, beginning with virtual screening of approved drugs against EtfD, followed by molecular docking, and concluding with molecular dynamics (MD) simulations. Virtual screening and molecular docking against a database of approved drugs identified diacerein, levonadifloxacin, and gatifloxacin as promising candidates for repurposing against TB. The MD simulations revealed stable binding of these compounds to EtfD, supported by hydrogen bonding and hydrophobic interactions. Binding free energy calculations and ADMET analyses further confirmed their potential efficacy and safety for TB treatment. Diacerein and levonadifloxacin, previously unexplored in anti-tuberculous therapy, alongside gatifloxacin, known for its efficacy in drug-resistant TB, emerged as promising candidates. Their broad-spectrum antimicrobial properties and favorable pharmacokinetic profiles suggest potential as alternatives to current TB treatments, especially against resistant strains. This study underscores the efficacy of computational drug repurposing, highlighting bacterial energy metabolism and lipid catabolism as fruitful targets. Further research is necessary to validate the clinical suitability and efficacy of diacerein, levonadifloxacin, and gatifloxacin, potentially enhancing the arsenal against global TB.