Computational investigation of phytomolecules as resuscitation-promoting factor B (RpfB) inhibitors for clinical suppression of Mycobacterium tuberculosis dormancy reactivation.

Among the various strategies of curbing tuberculosis, suppression of Mycobacterium tuberculosis (Mtb) is a primary goal of the WHO to stop its infection, which is further strengthened by the presence of a massive reservoir of latently infected individuals. Several efforts have been made to explore potential candidates, including drug-repurposing, phytomolecules evaluation, and de novo designs. Compared to other strategies, investigation of phytomolecules with known experimental evidence represents a highly cost-effective and less time-consuming approach. Interestingly, some of the phytomolecules, previously known to show anti-tuberculosis effects, are known. While, these compounds have not yet been tested for their additional abilities to interact with resuscitation-promoting factor B (RpfB), an essential protein involved in revoking of Mtb dormancy. We, therefore, performed an initial computational study to evaluate the binding affinity of 38 phytomolecules to select the most effective ligands against RpfB. The studies were carried out using AutoDock and associated tools for static interaction analysis, while molecular dynamics (MD) simulations were performed to examine the stability of predicted protein-ligand complexes using the Desmond MD package. As an outcome of this study, we have reported four potential compounds, viz. diospyrin, 2'-Nortiliacorinine, 5,4'-dihydroxy-3,7,8,3'-tetramethoxyflavone, and tiliacorine which showed a putative binding affinity with significant intermolecular interactions, docking energy of -8.0 kcal/mol or higher, and vital complex stability (~2.4 Å RMSD) during 100 ns MD simulation. The findings of this study indicated that phytomolecules are capable to efficiently inhibit the RpfB, which is vital for reactivation of dormant Mtb. Characterization of the molecular targets for hits with intriguingly selective activity against dormant Mtb would be helpful to elucidate the essential mechanisms underlying the survival of dormant Mtb during latent infections.