The derivatives of oseltamivir design passing through the important cleft of neuraminidase against influenza virus by de novo design
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 ”dosed” form when enzyme is binding with a ligand.Consequently, it would be a better strategy to design multi-binding-siteinhibitors 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 opfmal fragments with de novo design techniquc.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 Glu1 19 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.
H5N1 neuraminidase subtype 1 influenza virus 150-cavity de novo design dual-site-binding inhibitor oseltamivir
Wei-Bing Zhang Wen-Bo Liu Jing-Wei Wu Wei-Li Dong Shu-Qing Wang Run-Ling Wang
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R.China
国内会议
苏州
英文
447-456
2014-10-26（万方平台首次上网日期，不代表论文的发表时间）