| Abstract: |
Highlights: What are the main findings? M3 among all screened natural product based compounds, demonstrated the strongest binding affinity and stability with DosR protein. M3 outperformed reference compound Ursolic acid in molecular docking, MD Simulation and MM/GBSA. What is the implication of the main finding? M3 emerges as a potential candidate for further experimental studies against LTBI. Targeting DosR-regulated dormancy mechanisms could contribute to the development of more effective treatments against LTBI. Dormancy occurs when Mycobacterium tuberculosis (Mtb) enters a non-replicating and metabolically inactive state in response to hostile environment. During this state, it is highly resistant to conventional antibiotics, which increase the urgency to develop new potential drugs against dormant bacilli. In view of this, the dormancy survival regulator (DosR) protein is thought to be an essential component that plays a key role in bacterial adaptation to dormancy during hypoxic conditions. Herein, the NP-lib database containing natural product compounds was screened virtually against the binding site of the DosR protein using the MTiopen screen web server. A series of computational analyses were performed, including redocking, intermolecular interaction analysis, and MDS, followed by binding free energy analysis. Through screening, 1000 natural product compounds were obtained with docking energy ranging from −8.5 to −4.1 kcal/mol. The top four lead compounds were then selected for further investigation. On comparative analysis of intermolecular interaction, dynamics simulation and MM/GBSA calculation revealed that M3 docked with the DosR protein (docking score = −8.1 kcal/mol, RMSD = ~7 Å and ΔG Bind = −53.51 kcal/mol) exhibited stronger stability than reference compound Ursolic acid (docking score = −6.2 kcal/mol, RMSD = ~13.5 Å and ΔG Bind = −44.51 kcal/mol). Hence, M3 is recommended for further validation through in vitro and in vivo studies against latent tuberculosis infection. © 2025 by the authors. |
