Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1

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	Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1
	Li Y(李嫣) ; Zhou BC(周炳城) ; Wang RX(王任小)
刊名	J. Mol. Graph.
	2009
卷号	28 期号:3 页码:203-219
ISSN号	1093-3263
其他题名	Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1
通讯作者	王任小
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.
学科主题	计算机化学与化学信息学
收录类别	SCI
原文出处	http://dx.doi.org/10.1016/j.jmgm.2009.07.001
语种	英语
WOS记录号	WOS:000271349300001
公开日期	2013-08-29
内容类型	期刊论文
源URL	[http://202.127.28.38/handle/331003/28705]
专题	上海有机化学研究所_计算机化学与化学信息学研究室
推荐引用方式 GB/T 7714	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.
APA	李嫣,周炳城,&王任小.(2009).Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1.J. Mol. Graph.,28(3),203-219.
MLA	李嫣,et al."Rational design of Tamiflu derivatives targeting at the open conformation of neuraminidase subtype 1".J. Mol. Graph. 28.3(2009):203-219.