Li Ming, Wen Fang, Zhao Shengguo, Wang Pengpeng, Li Songli, Zhang Yangdong, Zheng Nan, Wang Jiaqi
Ministry of Agriculture Laboratory of Quality & Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China.
Int J Mol Sci. 2016 Jul 19;17(7):1078. doi: 10.3390/ijms17071078.
Targeting threonyl-tRNA synthetase (ThrRS) of Brucella abortus is a promising approach to developing small-molecule drugs against bovine brucellosis. Using the BLASTp algorithm, we identified ThrRS from Escherichia coli (EThrRS, PDB ID 1QF6), which is 51% identical to ThrRS from Brucella abortus (BaThrRS) at the amino acid sequence level. EThrRS was used as the template to construct a BaThrRS homology model which was optimized using molecular dynamics simulations. To determine the residues important for substrate ATP binding, we identified the ATP-binding regions of BaThrRS, docked ATP to the protein, and identified the residues whose side chains surrounded bound ATP. We then used the binding site of ATP to virtually screen for BaThrRS inhibitors and got seven leads. We further characterized the BaThrRS-binding site of the compound with the highest predicted inhibitory activity. Our results should facilitate future experimental effects to find novel drugs for use against bovine brucellosis.
靶向流产布鲁氏菌的苏氨酰 - tRNA合成酶（ThrRS）是开发抗牛布鲁氏菌病小分子药物的一种有前景的方法。使用BLASTp算法，我们从大肠杆菌中鉴定出ThrRS（EThrRS，PDB ID 1QF6），其在氨基酸序列水平上与流产布鲁氏菌的ThrRS（BaThrRS）有51%的同一性。以EThrRS为模板构建BaThrRS同源模型，并使用分子动力学模拟对其进行优化。为了确定对底物ATP结合重要的残基，我们鉴定了BaThrRS的ATP结合区域，将ATP对接至该蛋白，并鉴定了其侧链围绕结合的ATP的残基。然后我们利用ATP的结合位点虚拟筛选BaThrRS抑制剂，得到了7个先导化合物。我们进一步表征了预测抑制活性最高的化合物与BaThrRS的结合位点。我们的结果应有助于未来寻找抗牛布鲁氏菌病新药的实验研究。
