Qiu Yaping, Zhou Lu, Hu Yanqiu, Bao Yinfeng
a College of Chemical Engineering, Sichuan University , Chengdu , China.
J Recept Signal Transduct Res. 2019 Apr;39(2):154-166. doi: 10.1080/10799893.2019.1638404. Epub 2019 Jul 29.
Asbtract Filamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50 ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process.
丝状温度敏感蛋白Z（FtsZ）在细菌细胞分裂中起关键作用，被视为抗菌剂设计的一个有前景的靶点。本研究旨在寻找潜在的高效FtsZ抑制剂。本文采用基于配体的药效团和电子药效团、虚拟筛选和分子对接来检测有前景的FtsZ抑制剂，并利用分子动力学模拟研究蛋白质-配体复合物的稳定性。收集了来自已发表文献的63种抑制剂，其pIC范围为2.483至5.678，用于构建基于配体的药效团模型。选择与9PC结合的4DXD来构建电子药效团模型。通过测试集方法和诱饵集验证的药效团模型用于虚拟筛选，以排除针对ZINC数据库的无活性化合物。经过分子对接、ADME分析、诱导契合对接和MM-GBSA，确定了8个命中物作为有效的FtsZ抑制剂。对这些化合物进行了50纳秒的分子动力学模拟，以评估有效抑制剂与FtsZ之间的稳定性。结果表明，候选化合物具有较高的对接分数，并通过与关键氨基酸残基形成氢键相互作用而与FtsZ强烈结合，范德华力和疏水相互作用对结合稳定性有显著贡献。分子动力学模拟结果表明，蛋白质-配体化合物在模拟过程的稳定性和灵活性方面表现良好。
