DprE1 Enzyme a Potential Target for Treating Tuberculosis: A Drug Repurposing Approach

Tuberculosis (TB), a serious infectious disease caused by Mycobacterium tuberculosis, which is challenging to treat due to its complex cell wall which is essential for bacterial survival and its resistance towards anti-tb drugs. The enzyme DprE1, crucial for mycolic acid synthesis in their cell wall, is a promising drug target. This study used an in-silico drug repurposing approach, screening 7,647 FDA-approved drugs and phytochemicals against DprE1. The DprE1 structure was refined via I-TASSER and YASARA, and validated with ProSA and PDBsum. Molecular docking with AutoDock Vina identified 11 compounds with strong binding affinities (≤ –18.8 kcal/mol), outperforming the reference inhibitor BTZ (–10.05 kcal/mol). Amphotericin B showed the highest binding affinity (–21.34 kcal/mol) and stable interactions in 100.1 ns MD simulations. Other promising candidates included Nystatin, Rifapentine, and Eltrombopag. In-vitro and in-vivo analyses further supported their potential highlighting the value of drug repurposing in accelerating TB drug discovery targeting DprE1.