Luo Aoqi, Qian Chenliang, Zhang Zhenyu, Xia Jie, Jin Hongwei, Si Xinxin, Ma Shaojie
Jiangsu Key Laboratory of Marine Bioresources and Environment, Jiangsu Key Laboratory of Marine Biotechnology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, Jiangsu, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Chem Biodivers. 2025 Jun;22(6):e202403042. doi: 10.1002/cbdv.202403042. Epub 2025 Feb 6.
The filamentous temperature-sensitive protein Z (FtsZ) plays a vital role in bacterial division, making it an important antibacterial target. The inhibitor activity targeting the cleft between the H7 helix and the C-terminal substructural domain exhibited superior binding compared to the GTP binding site. This highlights the potential of the cleft as a promising target for further inhibitor discovery. In this study, we established a virtual screening (VS) pipeline using Discovery Studio software and employed FRED for molecular docking and Functional-Class Fingerprints_6 (FCFP_6) for molecular clustering, resulting in the identification of 38 potentially active compounds. These 38 compounds were then subjected to the following FtsZ inhibition assays, resulting in the four active compounds B6, B21, B26, and B31. Further experiments showed that compounds B6 and B26 exhibited antimicrobial activity with minimum inhibitory concentration (MIC) values of 8 and 32 µg/mL. Finally, molecular dynamics (MD) was used to analyze the binding modes of the protein-ligand. In addition, we predicted the physicochemical properties and toxicity of B6 and B26. In summary, our study successfully identified novel FtsZ inhibitors with antimicrobial activity through VS and in vitro biological evaluation, demonstrating their potential for further investigation.
丝状温度敏感蛋白Z（FtsZ）在细菌分裂中起着至关重要的作用，使其成为重要的抗菌靶点。与GTP结合位点相比，靶向H7螺旋与C末端亚结构域之间裂隙的抑制剂活性表现出更强的结合能力。这突出了该裂隙作为进一步发现抑制剂的有前景靶点的潜力。在本研究中，我们使用Discovery Studio软件建立了虚拟筛选（VS）流程，并采用FRED进行分子对接，使用功能类指纹_6（FCFP_6）进行分子聚类，从而鉴定出38种潜在活性化合物。然后对这38种化合物进行以下FtsZ抑制试验，得到了四种活性化合物B6、B21、B26和B31。进一步实验表明，化合物B6和B26表现出抗菌活性，最低抑菌浓度（MIC）值分别为8和32μg/mL。最后，利用分子动力学（MD）分析蛋白质 - 配体的结合模式。此外，我们预测了B6和B26的物理化学性质和毒性。总之，我们的研究通过虚拟筛选和体外生物学评价成功鉴定出具有抗菌活性的新型FtsZ抑制剂，证明了它们进一步研究的潜力。
