Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
J Chem Inf Model. 2012 Oct 22;52(10):2715-29. doi: 10.1021/ci300375k. Epub 2012 Oct 2.
The outbreak and high speed global spread of the new strain of influenza A/H1N1 virus in 2009 posed a serious threat to global health. It is more likely that drug-resistant influenza strains will arise after the extensive use of anti-influenza drugs. Consequently, the identification of the potential resistant sites for drugs in advance and the understanding of the corresponding molecular mechanisms that cause drug resistance are quite important in the design of new drug candidates with better potency to combat drug resistance. Here, we performed molecular simulations to evaluate the potency of oseltamivir to combat drug resistance caused by the mutations in 2009 A/H1N1 neuraminidase (NA). We examined three representative drug-resistant mutations in NA, consisting of H274Y, N294S, and Y252H. First, a theoretical structure of A/H1N1 NA in complex with oseltamivir was constructed using homology modeling. Then, molecular dynamics (MD) simulations, molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations, and MM/GBSA free energy decomposition were used to characterize the binding of oseltamivir with the wild type (WT) and three mutated NAs. Our predictions show that N294S and H274Y, two popular drug-resistant mutations in different variants of NA, still cause significant resistance to oseltamivir. However, the Y252H mutation does not impair the interactions between oseltamivir and A/H1N1 NA. An examination of individual energy components shows that the loss of polar interactions is the key source for the resistance of the studied mutations to oseltamivir. Moreover, free energy decomposition analysis and structural analysis reveal that the N294S or H274Y mutation triggers the large-scale conformational changes of the binding pocket and then impairs the affinity of oseltamivir. We expect that our results will be useful for the rational design of NA inhibitors with high potency against drug-resistant A/H1N1 mutants.
2009 年甲型 H1N1 流感新菌株的爆发和快速全球传播对全球健康构成了严重威胁。在广泛使用抗流感药物后，更有可能出现耐药流感株。因此，提前确定药物的潜在耐药部位，并了解导致耐药性的相应分子机制，对于设计具有更好疗效的新型候选药物以对抗耐药性非常重要。在这里，我们进行了分子模拟，以评估奥司他韦对抗 2009 年甲型 H1N1 神经氨酸酶 (NA) 突变引起的耐药性的效力。我们研究了 NA 中的三种代表性耐药突变，包括 H274Y、N294S 和 Y252H。首先，使用同源建模构建了甲型 H1N1 NA 与奥司他韦复合物的理论结构。然后，使用分子动力学 (MD) 模拟、分子力学/泊松-玻尔兹曼表面面积 (MM/PBSA) 计算和 MM/GBSA 自由能分解来表征奥司他韦与野生型 (WT) 和三种突变 NA 的结合。我们的预测表明，N294S 和 H274Y 是不同 NA 变体中两种流行的耐药突变，仍然对奥司他韦产生显著耐药性。然而，Y252H 突变不会损害奥司他韦与甲型 H1N1 NA 之间的相互作用。对单个能量成分的检查表明，极性相互作用的丧失是研究突变对奥司他韦产生耐药性的关键来源。此外，自由能分解分析和结构分析表明，N294S 或 H274Y 突变会引发结合口袋的大规模构象变化，从而降低奥司他韦的亲和力。我们希望我们的结果将有助于设计针对耐药性甲型 H1N1 突变体具有高效力的 NA 抑制剂。
