The derivatives of oseltamivir design passing through the important cleft of neuraminidase against influenza virus by de novo design

作者：Zhang, Wei-Bing; Liu, Wen-Bo; Wu, Jing-Wei; Dong, Wei-Li; Wang, Shu-Qing^*; Wang, Run-Ling

来源：Molecular Simulation, 2014, 40(15): 1209-1217.

DOI：10.1080/08927022.2013.854896

• H5N1
• neuraminidase subtype 1
• influenza virus
• 150-cavity
• de novo design
• dual-site-binding inhibitor
• oseltamivir

Owing to its unique function to release the progeny virus particles from the surface of an infected cell, neuraminidase has drawn special attention for developing new drugs to treat influenza viruses. The 150-cavity that is adjacent to the active pocket of the group-1 neuraminidase (N1) renders the conformational change from 'open' form to 'closed' form when enzyme is binding with a ligand. Consequently, it would be a better strategy to design multi-binding-site inhibitors including X and R groups with proper shapes, sizes and electronic charges fitting into the active site. The NCI and ZINC fragment databases were screened for finding the optimal fragments with de novo design technique. By doing so, 24 derivatives of oseltamivir were obtained by linking the fragments at two different sites of the scaffold of oseltamivir. Molecular docking and dynamics showed that these compounds not only adopt more favourable conformation but also have stronger binding interaction with receptor. Most importantly, all compounds skilfully pass through the cleft (formed by Glu119 and Arg156) and fit into 150-cavity. Therefore, the selected 24 derivatives may become promising candidates for treating influenza virus; in addition, the findings reported here may at least provide useful insights and stimulate new strategy in this area.

• 出版日期2014
• 单位天津医科大学