Liu Chi, He Gu, Jiang Qinglin, Han Bo, Peng Cheng
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Int J Mol Sci. 2013 Jul 9;14(7):14225-39. doi: 10.3390/ijms140714225.
Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents.
甲硫氨酸tRNA合成酶（MetRS）是所有生物中参与蛋白质生物合成的一种必需酶，也是一个潜在的抗菌靶点。在当前研究中，已提出基于结构的药效团（SBP）引导方法，以基于MetRS-抑制剂复合物的14个晶体结构生成MetRS的综合药效团。在本研究中，一种虚拟筛选方法的混合方案，包括基于药效团模型的虚拟筛选（PBVS）、基于刚性和柔性对接的虚拟筛选（DBVS），用于从商业化学数据库中检索新的MetRS抑制剂。然后将这种混合虚拟筛选方法应用于筛选Specs（202,408种化合物）数据库，这是一个结构多样的化学数据库。从最终命中物中选择了15种命中化合物并转向实验研究。这些结果可能为进一步研究新型MetRS抑制剂作为抗菌剂提供重要信息。
