当前位置: X-MOL 学术J. Recept. Signal Transduct. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Novel and potent inhibitors for dihydropteroate synthase of Helicobacter pylori
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-02-26 , DOI: 10.1080/10799893.2020.1731533
Sri Harsha Satuluri 1 , Sudheer Kumar Katari 1 , Chiranjeevi Pasala 1 , Umamaheswari Amineni 1
Affiliation  

Abstract An endless drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of H. pylori infections, thereby ambitious novel proof-of-concept for inhibitor design was practiced in advancement of medication. Dihydropteroate synthase (DHPS) is an alluring target that plays a great role in folate synthesis pathway essential for amino acids biosynthesis was selected for designing novel drugs to prevent infections caused by pathogenic H. pylori. In the present study, a reliable tertiary structure of DHPS in complex with inhibitor 6MB was constructed by Modeler 9v19. DrugBank compounds of DHPS, published inhibitors, and co-crystal ligand (6MB) were docked against DHPS. The best docked compounds were screened against 28.5 million compounds resulted 1186 structural analogs. Virtual screening workflow and quantum polarized ligand dockings of these compounds against DHPS resulted three leads that showed better XP Gscores, ADME properties, and binding-free energies compared to 6MB, DrugBank compounds, and published inhibitors. The proposed leads were also validated by receiver operative characteristic (ROC) curve metrics in the presence of thousand decoys and the best docked existing compounds against DHPS. Long-range molecular dynamics (MD) simulations for 100 ns were executed after post-docking evaluations. Trajectory analysis showed the lead–DHPS docking complex’s inter-molecular interactions were stable throughout the entire runtime of MD simulations than 6MB–DHPS complex and Eliglustat–DHPS complex. The study outcomes showed good competitive binding propensity and active-tunneling of leads over the existing inhibitors, thereby these leads could be ideal inhibitors against DHPS to target H. pylori.

中文翻译:

幽门螺杆菌二氢蝶酸合酶的新型有效抑制剂

摘要 无尽的幽门螺杆菌耐药菌株和众多的药物反应是治疗幽门螺杆菌感染的障碍,因此在药物的进步中实践了雄心勃勃的抑制剂设计的新概念验证。二氢蝶酸合酶 (DHPS) 是一种诱人的靶点,在氨基酸生物合成所必需的叶酸合成途径中起着重要作用,被选择用于设计预防致病性幽门螺杆菌引起的感染的新型药物。在本研究中,与抑制剂 6MB 复合的 DHPS 的可靠三级结构由 Modeler 9v19 构建。DHPS 的 DrugBank 化合物、已发表的抑制剂和共晶配体 (6MB) 与 DHPS 对接。针对 2850 万种化合物筛选了最佳对接化合物,产生了 1186 种结构类似物。这些化合物针对 DHPS 的虚拟筛选工作流程和量子极化配体对接产生了三个线索,与 6MB、DrugBank 化合物和已发表的抑制剂相比,这些线索显示出更好的 XP Gscores、ADME 特性和无结合能量。在存在数千个诱饵和针对 DHPS 的最佳对接现有化合物的情况下,还通过接受者操作特征 (ROC) 曲线指标验证了提议的引线。在对接后评估后执行了 100 ns 的长程分子动力学 (MD) 模拟。轨迹分析表明,在整个 MD 模拟运行期间,铅-DHPS 对接复合物的分子间相互作用比 6MB-DHPS 复合物和 Eliglustat-DHPS 复合物稳定。
更新日期:2020-02-26
down
wechat
bug