Kulandaisamy Rajkumar, Kushwaha Tushar, Kumar Manoj, Polamarasetty Aparoy, Kumar Saroj, Gholap Shivajirao L, Appaiahgari Mohan B, De Soumya, Inampudi Krishna Kishore
All India Institute of Medical Sciences, Department of Biophysics, New Delhi, 110029, Delhi, India.
Indian Institute of Petroleum and Energy, Faculty of Biology, Visakhapatnam, 530003, Andhra Pradesh, India.
ACS Omega. 2025 Aug 14;10(33):37115-37127. doi: 10.1021/acsomega.5c01747. eCollection 2025 Aug 26.
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 . 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.
细菌的翻译机制在其生存中起着至关重要的作用，使其成为抗生素开发的一个有吸引力的靶点。翻译过程可能会因各种因素而停止，导致核糖体停滞并释放致死性肽基 - tRNA。肽基tRNA水解酶（PtH）切割肽基 - tRNA中肽与tRNA之间的酯键以拯救细胞。因此，靶向这种酶在对抗耐药细菌方面具有巨大潜力，因为它代表了一个新的靶点并且在细菌生存中起着不可或缺的作用。在本研究中，我们虚拟筛选了三个不同的数据库：DrugBank、Maybridge和ZINC天然产物数据库，以从……中鉴定PtH的潜在抑制剂。我们通过分子动力学（MD）模拟评估了从筛选中获得的PtH - 抑制剂复合物的稳定性。此外，我们估计了它们的结合能并进行了逐个残基分解以了解单个氨基酸的贡献。我们还评估了排名前十的潜在抑制剂的ADMET性质和药物相似性。尽管目前尚待实验验证，但这项研究代表了朝着开发强效且特异性的PtH抑制剂迈出的重要一步。
