Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF03NB, UK.
J Mol Model. 2011 Jul;17(7):1679-93. doi: 10.1007/s00894-010-0871-9. Epub 2010 Nov 2.
Treatment of C. difficile infection is one of the most difficult biomedical challenges. To develop novel antibacterials, researchers have been targeting bacterial molecular functions that are essential for its growth. The methionyl tRNA synthetase (MetRS) is strictly required for protein biosynthesis and success was reported in developing antibacterials to inhibit this enzyme. The present study was aimed at building and analyzing a homology model for C. difficile MetRS in the context of drug design. A homology model of C. difficile MetRS was constructed using Molecular Operating Environment (MOE) software. A. aeolicus MetRS was the main template while the query zinc binding domain was modeled using T. thermophilus MetRS. The model has been assessed and compared to its main template (Ramachandran, ERRAT and ProSA). The active site of the query protein has been predicted from its sequence using a detailed conservation analysis (ClustalW2). Using MOE software, suitable ligands were docked in the constructed model, including a C. difficile MetRS inhibitor REP3123 and the enzyme natural substrate, and the key active site residues and interactions were identified. These docking studies have validated the active site conformation in the constructed model and identified binding interactions.
艰难梭菌感染的治疗是最具挑战性的生物医学难题之一。为了开发新型抗菌药物，研究人员一直致力于针对细菌生长所必需的分子功能。甲硫氨酰-tRNA 合成酶（MetRS）是蛋白质生物合成所必需的，并且已有研究成功开发出抑制该酶的抗菌药物。本研究旨在构建和分析艰难梭菌 MetRS 的同源模型，以进行药物设计。使用分子操作环境（MOE）软件构建了艰难梭菌 MetRS 的同源模型。主要模板为 A. aeolicus MetRS，查询锌结合结构域使用 T. thermophilus MetRS 建模。该模型已进行评估，并与主要模板（Ramachandran、ERRAT 和 ProSA）进行了比较。使用 ClustalW2 对查询蛋白的活性位点进行了详细的保守性分析，预测了序列中的活性位点。使用 MOE 软件，将合适的配体对接在构建的模型中，包括艰难梭菌 MetRS 抑制剂 REP3123 和酶的天然底物，并确定了关键的活性位点残基和相互作用。这些对接研究验证了构建模型中活性位点的构象，并确定了结合相互作用。
