Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
J Mol Graph Model. 2022 Jul;114:108189. doi: 10.1016/j.jmgm.2022.108189. Epub 2022 Apr 14.
Bacterial resistance caused by widespread use and abuse of antibiotics is threatening human health, and the development of new antibacterial agents with novel antibacterial targets has become urgent. Filamenting temperature-sensitive mutant Z (FtsZ), as a key protein in bacterial division, has received extensive attention. PC190723 exhibits an outstanding antibacterial activity by producing potent inhibitory ability on FtsZ protein, but its influence on the conformation of FtsZ protein at the molecular level is still unclear. In this study, we explored the effect of PC190723 on the conformation and function of FtsZ protein through molecular dynamics (MD) simulation and post-analysis. The results showed that PC190723 increased the high-affinity conformational stability of FtsZ protein, which disrupts the normal assembly of the Z-ring. In particular, the interactions of residues S8-sheet (VAL260-GLY266) increased in the FtsZ system, which may be the reason for promotes the formation of protofilament. In brief, the mechanism of PC190723 inhibiting FtsZ protein was explained at the molecular level by MD simulation, which provides new ideas for the identification of new FtsZ inhibitors as antibacterial agents.
抗生素的广泛使用和滥用导致的细菌耐药性正威胁着人类健康，因此开发具有新型抗菌靶点的新型抗菌剂迫在眉睫。丝状温度敏感突变体 Z（FtsZ）作为细菌分裂的关键蛋白，受到了广泛关注。PC190723 通过对 FtsZ 蛋白产生强大的抑制能力表现出出色的抗菌活性，但它对 FtsZ 蛋白构象的影响在分子水平上仍不清楚。在这项研究中，我们通过分子动力学（MD）模拟和后续分析探讨了 PC190723 对 FtsZ 蛋白构象和功能的影响。结果表明，PC190723 增加了 FtsZ 蛋白的高亲和力构象稳定性，从而破坏了 Z 环的正常组装。特别是 FtsZ 系统中 S8 片层（VAL260-GLY266）残基的相互作用增加，这可能是促进原丝形成的原因。总之，通过 MD 模拟从分子水平解释了 PC190723 抑制 FtsZ 蛋白的机制，为鉴定新型 FtsZ 抑制剂作为抗菌剂提供了新的思路。
