Targeting a cluster of arginine residues of neuraminidase to avoid oseltamivir resistance in influenza A (H1N1): a theoretical study
Targeting a cluster of arginine residues of neuraminidase to avoid oseltamivir resistance in influenza A (H1N1): a theoretical study
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DOI：
10.1007/s00894-014-2525-9
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发表时间：
2015-01-01
影响因子：
2.2
通讯作者：
Correa-Basurto, J.
中科院分区：
文献类型：
--
作者：
Gema, L. Ramirez-Salinas;Tolentino-Lopez, L. E.;Correa-Basurto, J.
2009 年甲型 H1N1 流感在墨西哥和世界各地大流行后，奥司他韦耐药临床病例数量有所增加，其机制尚不清楚。在这项工作中，我们重点研究突变的 NA 结构 ADA71175 (GenBank) 和 3CKZ (PDB ID)。最近结晶的 NA (PDB ID: 3NSS) 被用作野生型结构和模板来构建 ADA71175 的三维 (3D) 结构。然后，将 NA 突变体和 3NSS 天然体以及通过 MD 模拟（50 ns 的快照）确定的精细单体结构用作模型，使用一组芳基奥司他韦衍生物进行对接研究。这些芳基奥司他韦衍生物比奥司他韦具有更好的识别特性，因为在结合位点与一簇精氨酸残基（118、292 和 371）存在阳离子-π 相互作用。该 Arg 残基簇代表芳基奥司他韦衍生物的潜在结合位点，芳基奥司他韦衍生物可能是新型 NA 抑制剂。
Following the influenza A (H1N1) pandemic in Mexico and around the world in 2009, the numbers of oseltamivir-resistant clinical cases have increased through a mechanism that remains unclear. In this work, we focus on studying the mutated NA structures ADA71175 (GenBank) and 3CKZ (PDB ID). Recently crystallized NA (PDB ID: 3NSS) was used as a wildtype structure and template to construct the three-dimensional (3D) structure of ADA71175. Then, the NA mutants and 3NSS natives as well as their refined monomer structures as determined through MD simulations (snapshots at 50 ns) were used as models to perform a docking study using a set of aryl-oseltamivir derivatives. These aryl-oseltamivir derivatives have better recognition properties than oseltamivir because of cation-pi interactions with a cluster of Arg residues (118, 292, and 371) at the binding site. This cluster of Arg residues represents a potential binding site for aryl-oseltamivir derivatives that are potentially new NA inhibitors.