Inhibition of <i>Mycobacterium tuberculosis</i> Cell Wall Biosynthesis by Repurposing Drugs: Molecular Docking, Simulation, and 3D QSAR

Abstract Mycobacterium tuberculosis remains a serious global health challenge, responsible for millions of tuberculosis cases annually. The enzyme embB is critical in the biosynthesis of arabinogalactan, a key component of the mycobacterial cell envelope, and is linked to resistance against the antituberculosis drug ethambutol. This study explored the inhibitory potential of FDA approved drugs and their analogues against embB. Among all drugs, dihydroergotamine scored the highest, with a XP docking score of −7.356 kcal/mol. The study was extended to identify analogues of dihydroergotamine and was sourced from PubChem. The dihydroergotamine analogues PubChem CID 5319635 (−11.355 kcal/mol) and 182505 (−8.214 kcal/mol) with high docking scores were selected and molecular dynamics simulations were performed for 150 ns to verify the stability of the interactions. Additionally, a 3D quantitative structure–activity relationship (3D QSAR) analysis was performed with indole alkaloids and their derivatives exhibiting antitubercular properties, resulting in a reliable field‐based model. Using this model, predicted pMIC values for CID 5319635 (pMIC: 4.913) and CID 182505 (pMIC: 5.285) were found to be better than the experimental pMIC of ethambutol (4.407). The study thus concludes that CID 5319635 and CID 182505 form stable complexes with embB, positioning them as promising lead compounds for tuberculosis treatment.