Kumari Madhulata, Chandra Subhash, Tiwari Neeraj, Subbarao Naidu
Department of Information Technology, Kumaun University, SSJ Campus, Almora, Uttarakhand 263601, India.
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Bioinformation. 2017 Jan 20;13(1):8-16. doi: 10.6026/97320630013008. eCollection 2017.
The Brucella melitensis methionyl-tRNA-synthetase (MetRSBm) is a promising target for brucellosis drug development. The virtual screening of large libraries of a drug like molecules against a protein target is a common strategy used to identify novel inhibitors. A High throughput virtual screening was performed to identify hits to the potential antibrucellosis drug target, MetRSBm. The best inhibitor identified from the literature survey was 1312, 1415, and 1430. In the virtual screening 56,400 compounds of ChEMBL antimycobacterial library, 1596 approved drugs, 419 Natural product IV library, and 2396 methionine analogous were docked and rescoring, identified top 10 ranked compounds as anti-mycobacterial leads showing G-scores -10.27 to -8.42 (in kcal/mol), approved drugs G-scores -9.08 to -6.60 (in kcal/mol), Natural product IV library G-scores -10.55 to -6.02 (in kcal/mol), methionine analogous Gscores -11.20 to -8.51 (in kcal/mol), and compared with all three known inhibitors (as control) G-scores -3.88 to -3.17 (in kcal/mol). This result indicates these novel compounds have the best binding affinity for MetRSBm. In this study, we extrapolate that the analogous of methionine for find novel drug likeness has been identified [4-(L-histidyl)-2-phenylbenzoyl] methionine hydrochloride, might show the inhibitor of Brucella melitensis effect by interacting with MetRS enzyme. We suggests that Prumycin as a natural product is the novel drugs for brucellosis.
羊种布鲁氏菌甲硫氨酰 - tRNA合成酶（MetRSBm）是布鲁氏菌病药物研发的一个有前景的靶点。针对蛋白质靶点对类似药物分子的大型文库进行虚拟筛选是用于鉴定新型抑制剂的常用策略。进行了高通量虚拟筛选以鉴定针对潜在抗布鲁氏菌病药物靶点MetRSBm的命中化合物。从文献调研中确定的最佳抑制剂为1312、1415和1430。在虚拟筛选中，对ChEMBL抗分枝杆菌文库的56,400种化合物、1596种已批准药物、419种天然产物IV文库和2396种甲硫氨酸类似物进行对接和重新评分，确定排名前10的化合物作为抗分枝杆菌先导物，其G值为 -10.27至 -8.42（千卡/摩尔），已批准药物的G值为 -9.08至 -6.60（千卡/摩尔），天然产物IV文库的G值为 -10.55至 -6.02（千卡/摩尔），甲硫氨酸类似物的G值为 -11.20至 -8.51（千卡/摩尔），并与所有三种已知抑制剂（作为对照）的G值 -3.88至 -3.17（千卡/摩尔）进行比较。该结果表明这些新型化合物对MetRSBm具有最佳结合亲和力。在本研究中，我们推断已鉴定出用于寻找新型药物相似性的甲硫氨酸类似物[4 -（L - 组氨酰）-2 - 苯基苯甲酰基]甲硫氨酸盐酸盐，它可能通过与MetRS酶相互作用而显示出对羊种布鲁氏菌的抑制作用。我们认为普鲁霉素作为一种天然产物是治疗布鲁氏菌病的新型药物。
