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学科主题: 计算机化学与化学信息学
题名: Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1
其他题名: Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1
作者: Li Y(李嫣) ; Zhou BC(周炳城) ; Wang RX(王任小)
通讯作者: 王任小
刊名: J. Mol. Graph.
发表日期: 2009
卷: 28, 期:3, 页:203-219
收录类别: SCI
部门归属: 上海有机所
英文摘要: Neuraminidase is an attractive therapeutic target for standing against influenza virus, such as the threatening avian influenza virus H5N1. A recently discovered cavity near the well-known catalytic site on neuraminidase subtype I (N1) provides a good possibility to develop dual-site-binding inhibitors, which may achieve improved activities and selectivities against N1. We have designed some derivatives of Tamiflu with such features through a fragment-based approach combining multiple computational methods. Over 1000 FDA-approved small-molecule drugs were computationally screened targeting at the open conformation of N1 with the COLD program in combination with the X-Score scoring function. Some chemical fragments on the top-scored hits, which were able to fit into the 150-cavity, were transplanted onto the core structure of Tamiflu to produce a total of 30 new molecules. Then, binding of these designed molecules to NI was evaluated by molecule docking. The promising ones were further subjected to molecular dynamics simulation of 3 ns long, and their binding free energies were computed by using the MM-PB/SA method. Some of our designed molecules were predicted to have comparable or even better binding affinities than that of Tamiflu. We report our results herein so that other researchers who have the necessary chemical and biological resources can utilize them in the development of new N1 inhibitors. In addition, our study actually suggests a practical strategy for optimizing a given lead compound based on the outcomes of a standard virtual screening trial. (C) 2009 Elsevier Inc. All rights reserved.
语种: 英语
相关网址: 查看原文
WOS记录号: WOS:000271349300001
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/28705
Appears in Collections:计算机化学与化学信息学研究室_期刊论文

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Recommended Citation:
Li Y,Zhou BC,Wang RX. Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1[J]. J. Mol. Graph.,2009,28(3):203-219.
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