Abstract
Tuberculosis (TB) is a global health challenge associated with considerable levels of illness and mortality worldwide. The development of innovative therapeutic strategies is crucial to combat the rise of drug-resistant TB strains. DNA Gyrase A (GyrA) and serine/threonine protein kinase (PknB) are promising targets for new TB medications. This study employed techniques such as similarity searches, molecular docking analyses, machine learning (ML)-driven absolute binding-free energy calculations, and molecular dynamics (MD) simulations to find potential drug candidates. By combining ligand- and structure-based methods with ML principles and MD simulations, a novel strategy was proposed for identifying small molecules. Drugs with structural similarities to existing TB therapies were assessed for their binding affinity to GyrA and PknB through various docking approaches and ML-based predictions. A detailed analysis identified six promising compounds for each target, such as DB00199, DB01220, DB06827, DB11753, DB14631, and DB14703 for GyrA; and DB00547, DB00615, DB06827, DB14644, DB11753, and DB14703 for PknB. Notably, DB11753 and DB14703 show significant potential for both targets. Furthermore, MD simulations' statistical metrics confirm the drug-target complexes' stability, with MM-GBSA analyses underscoring their strong binding affinity, indicating their promise for TB treatment even though they were not initially designed for this disease.