Identification of potential alternatives for isoniazid: An in silico molecular dynamics study

Tuberculosis (TB) remains a major global health concern that affects millions and results in several casualties and these numbers are further increased because of the drug-resistant strains of Mycobacterium tuberculosis (M. tb). Current treatments, such as Isoniazid (INH), while effective, are increasingly compromised by resistance and associated side effects, emphasizing the urgent need for new therapeutic options. This study focuses on identifying novel inhibitors for the Enoyl-Acyl Carrier Protein Reductase (InhA), a crucial enzyme in mycobacterium cell wall biosynthesis. Using a combination of ligand-based and structure-based virtual screening, we screened a library of FDA-approved drugs to find potential alternatives to INH. Several promising compounds with superior binding affinities to the INH-NAD adduct were identified. These compounds underwent further refinement and analysis through molecular dynamics simulations, where their stability, binding interactions, and free energy profiles were thoroughly evaluated. Our simulations revealed that Bictegravir and Vibegron demonstrated strong electrostatic interactions and favourable binding energies, making them a potential candidate for TB treatment. This computational approach provides a foundation for discovering safer and more effective therapies against both drug-sensitive and drug-resistant TB strains.