Aboelnga Mohamed M, Gauld James W
Department of Chemistry, Faculty of Science, Damietta University, New Damietta, Egypt.
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Canada.
J Biomol Struct Dyn. 2024;42(24):13555-13563. doi: 10.1080/07391102.2023.2276878. Epub 2023 Nov 1.
Due to the growing interest in directing aminoacyl-tRNA synthetases for antimicrobial therapies, evaluating the binding proficiency of potential inhibitors against this target holds significant importance. In this work, we proposed potential ligands that could properly bind to the crucial Zn(II) cofactor located in the active site of Threonyl-tRNA synthetases (ThrRS), potentially functioning as competitive inhibitors. Initially, detailed DFT quantum chemical study was conducted to examine the binding ability of threonine against unnatural amino acids to cofactor Zn(II). Then, the binding energy value for each suggested ligand has been determined and compared to the value determined for the native substrate, threonine. Our screening investigation showed that the native threonine should coordinate in a bidentate fashion to this Zn(II) which lead to the highest (binding energy) BE Thereby, the synthetic site of ThrRS rejects unnatural amino acids that cannot afford this type of coordination to Zn(II) ion which has been supported by our calculations. Moreover, based on their binding to the Zn(II) and the obtained BE values compared to the cognate threonine, many potent ligands have been suggested. Importantly, ligands with deprotonated warheads showed the highest binding ability amongst a list of potential hits. Further investigation on the selected ligands using molecular docking and QM/MM calculations confirmed our findings of the suggested ligands being able to bind efficiently in the active site of ThrRS. The suggested hits from this study should be valuable in paving routs for developing candidates as competitive inhibitors against the bacterial ThrRS.Communicated by Ramaswamy H. Sarma.
由于将氨酰 - tRNA合成酶用于抗菌治疗的兴趣日益浓厚，评估潜在抑制剂与该靶点的结合能力具有重要意义。在这项工作中，我们提出了可能与苏氨酰 - tRNA合成酶（ThrRS）活性位点中的关键锌（II）辅因子正确结合的潜在配体，它们可能作为竞争性抑制剂发挥作用。最初，进行了详细的密度泛函理论（DFT）量子化学研究，以研究苏氨酸与非天然氨基酸对辅因子锌（II）的结合能力。然后，确定了每个建议配体的结合能值，并与天然底物苏氨酸的结合能值进行比较。我们的筛选研究表明，天然苏氨酸应以双齿方式与该锌（II）配位，从而导致最高的结合能。因此ThrRS的合成位点会排斥那些不能与锌（II）离子形成这种配位方式的非天然氨基酸，这一点已得到我们计算结果的支持。此外，基于它们与锌（II）的结合以及与同源苏氨酸相比获得的结合能值，提出了许多有效的配体。重要的是，在一系列潜在的命中配体中，带有去质子化弹头的配体显示出最高的结合能力。使用分子对接和QM/MM计算对所选配体进行的进一步研究证实了我们的发现，即所建议的配体能够在ThrRS的活性位点有效结合。本研究中建议的命中配体对于开发作为细菌ThrRS竞争性抑制剂候选物的途径应具有重要价值。由Ramaswamy H. Sarma传达。
