Repurposing FDA-Approved Drugs as Novel Inhibitors of the MbtB condensation/cyclization (Cy) Domain in Mycobacterium tuberculosis

Tuberculosis (TB) remains an universal health burden, requiring the development of novel therapeutic approaches to combat the drug resistance and to enhance the treatment outcomes. In this survey, we focused on the condensation/cyclization (Cy) domain of phenyloxazoline synthase MbtB, a key enzyme involved in biosynthetic pathway of mycobactin in Mycobacterium tuberculosis. The ligand binding pocket was identified using CavityPlus in the region between 96 and 394 on AlphaFold-predicted structure of MbtB. A comprehensive drug repurposing approach was employed using a library of FDA-approved compounds obtained from the ZINC database. Structure based High-throughput virtual screening was done using AutoDock-GPU on the GoogleColab. Compounds were prioritized based on their predicted binding affinities. The top 10 compounds were then further evaluated to molecular dynamics (MD) simulation for 300 ns. The MD trajectories were then analysed for stability of the complex and key intermolecular interactions. The free energy of binding for each complex was then calculated using MMPBSA/MMGBSA to identify the most favorable binders. The most promising hits identified through this computational pipeline will then be proposed for experimental validation as reported in our earlier publications using iron-rich and iron-deficient media. This integrated computational approach provides a cost-effective strategy for identifying potential anti-tubercular drug candidates targeting MbtB.