### 3MBA类FtsZ蛋白抑制剂的分子动力学模拟及抗菌作用机制

1. 天津理工大学化学化工学院, 天津 300384
• 收稿日期:2014-10-27 修回日期:2015-01-06 发布日期:2015-03-06
• 通讯作者: 卢俊瑞 E-mail:lujunrui@tjut.edu.cn
• 基金资助:

国家自然科学基金(21476174, 21176194)资助项目

### Molecular Dynamics Simulation and Antibacterial Mechanism of 3MBA Derivatives as FtsZ Protein Inhibitors

ZHANG He, LU Jun-Rui, MU Jiang-Bei, LIU Jin-Biao, YANG Xu-Yun, WANG Mei-Jun, ZHANG Rui-Bo

1. School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, P. R. China
• Received:2014-10-27 Revised:2015-01-06 Published:2015-03-06
• Contact: LU Jun-Rui E-mail:lujunrui@tjut.edu.cn
• Supported by:

The project was supported by the National Natural Science Foundation of China (21476174, 21176194).

Abstract:

In this paper, the complex stability, secondary structure, protein conformation, residue distance, active site volume, and binding free energy of the binary complex of filamentous sensitivity division protein Z of Staphylococcus aureus-guanosine diphosphate (SaFtsZ-GDP) and the ternary complex of SaFtsZ-GDP- 3MBA (3-methoxybenzamide) derivatives were studied using molecular dynamics simulations, definition of secondary structure of proteins (DSSP), pocket volume measurer (POVME), and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results show that the SaFtsZ-GDP binary complex was unstable in the absence of inhibitor, and the residues of its T7Loop area (residues 203-209) show obvious fluctuations. The secondary structure of the protein in the T7Loop area also changes significantly, the active pocket volume decreases dramatically and the substrate channel size becomes narrow and unstable. However, the SaFtsZ-GDP-3MBA derivatives ternary complex looks completely different in the presence of inhibitor PC190723 or Compound 1. Both of the inhibitors can form hydrogen bonds and hydrophobic interactions with high affinity to FtsZ. However, the ligand only forms hydrophobic interactions with partial residues of the active site as a function of simulation time in the SaFtsZ-GDP-3MBA ternary complex. This low affinity means that 3MBA cannot stably exist in the active site, and so the antibacterial activity of 3MBA is significantly lower than that of PC190723 or Compound 1. The study shows the antibacterial mechanism and effect of 3MBA derivatives on FtsZ, and provides an important theoretical basis for inhibitor structural optimization, development and applications.

MSC2000:

• O641