Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble.
Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble.
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DOI：
10.1111/j.1747-0285.2007.00614.x
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发表时间：
2008-02
影响因子：
3
通讯作者：
Vajda, Sandor
中科院分区：
文献类型：
--
作者：
Landon, Melissa R.;Amaro, Rommie E.;Baron, Riccardo;Ngan, Chi Ho;Ozonoff, David;McCammon, J. Andrew;Vajda, Sandor
关键词：
H5 N1亚型流感病毒由于其高毒力和突变率，引起了人们对可能的人类大流行威胁的关注。虽然几种已批准的抗流感药物有效地靶向神经氨酸酶，但一些菌株已经获得了对目前可用的抗流感药物的耐药性。在这项研究中，我们提出了协同应用扩展的显式溶剂分子动力学（MD）和计算溶剂映射（CS-Map），以确定假定的“热点”内的灵活结合区域的N1神经氨酸酶。使用代表性的构象的N1结合区提取的聚类分析的四个串联的40-ns MD模拟，CS-Map被用来评估的能力，小的溶剂大小的分子结合在紧密接近的唾液酸结合区。占主导地位的MD构象的映射分析揭示了在150-和430-环区域中存在额外的热点区域。我们的热点分析为开发能够结合这些区域的高亲和力抑制剂的可行性提供了进一步的支持，这些区域似乎是N1菌株所独有的。
The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain.
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DOI：
10.1073/pnas.062398499
发表时间：
2002-04-02
影响因子：
11.1
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
通讯作者：
Vajda, S
影响因子：
7.6
作者：
Carr, J;Ives, J;Roberts, N
通讯作者：
Roberts, N
影响因子：
7.3
作者：
GOODFORD, PJ
通讯作者：
GOODFORD, PJ
DOI：
10.1016/0167-4838(91)90526-6
发表时间：
1991-03-08
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CHONG, AKJ;PEGG, MS;VONITZSTEIN, M
通讯作者：
VONITZSTEIN, M
影响因子：
4.9
作者：
Govorkova, EA;Leneva, IA;Webster, RG
通讯作者：
Webster, RG