Acridone Alkaloids as Promising Dual Inhibitors of PknA and PknB ofM. tuberculosis: ADMET, Molecular Docking and Molecular Dynamics Studies

Tuberculosis (TB) continues to pose a significant global health challenge, largely owing to the increasing prevalence of drug-resistant strains that limit the effectiveness of current therapies. Addressing this problem requires the discovery of novel drugs with novel mechanisms of action. The serine/threonine protein kinases PknA and PknB are crucial for bacterial growth, cell wall synthesis, and survival, making them attractive targets for anti-TB drug development. In this study, we explored seven natural products derived from East African medicinal plants as potential inhibitors of PknA and PknB, using computational methods. This study evaluated pharmacokinetic and toxicity profiles to assess drug-likeness. Next, molecular docking was performed to determine binding affinities and identify key protein-ligand interactions. This was followed by molecular dynamics (MD) simulations to examine the stability of the promising complexes. Our results highlight two acridone alkaloids from Zanthoxylum leprieurii, natural product (NP), NP2 and NP3, as strong binders to both kinases. NP2 exhibited binding energies of −9.79 kcal/mol with PknA and −9.06 kcal/mol with PknB, while NP3 showed −10.18 kcal/mol and −9.93 kcal/mol, respectively. Both compounds stably interacted with essential catalytic residues, including those in the conserved DFG motif. MD simulations over 100 ns confirmed structural stability, with root mean square deviations (RMSD) values around 1.6 Å for NP2 and 1.8 Å for NP3. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis further supported their strong binding, revealing free energies lower than −80 kJ/mol, predominantly driven by van der Waals interactions. These findings suggest that NP2 and NP3 are promising dual inhibitors of PknA and PknB, exhibiting favorable drug-like properties and no hepatotoxicity. Further experimental validation, such as in vitro enzyme assays, is warranted to confirm their potential as lead compounds for anti-TB drug development.