In Silico Screening and Molecular Dynamics Simulations of Small Molecules Targeting Peptidyl tRNA Hydrolase for Drug-Resistant Tuberculosis.

The translation machinery of bacteria plays a crucial role in their survival, making it an attractive target for the development of antibiotics. The translation process may be halted due to various factors, leading to ribosome stalling and the release of lethal peptidyl-tRNA. Peptidyl tRNA hydrolase (PtH) cleaves the ester bond between the peptide and the tRNA in peptidyl-tRNA to rescue the cell. Therefore, targeting this enzyme holds significant potential for combating drug-resistant bacteria, as it represents a novel target and plays an indispensable role in bacterial survival. In this study, we virtually screened three different databases: DrugBank, Maybridge, and ZINC natural products to identify potential inhibitors of PtH from Mycobacterium tuberculosis. We evaluated the stability of the PtH-inhibitor complexes obtained from screening through Molecular Dynamics (MD) simulations. Furthermore, we estimated their binding energy and performed per-residue decomposition to understand the contributions of individual amino acids. We also assessed the top ten potential inhibitors for their ADMET properties and drug-likeness. Although experimental validation is currently pending, this study represents a significant step toward the development of potent and specific inhibitors of PtH.