Center for Bioinformatics and Molecular Simulation, Universidad de Talca, Chile.
J Chem Inf Model. 2012 Oct 22;52(10):2650-6. doi: 10.1021/ci300343w. Epub 2012 Oct 4.
New mutants of human influenza virus (A/H1N1) exhibit resistance to antiviral drugs. The mechanism whereby they develop insensitivity to these medications is, however, not yet completely understood. A crystallographic structure of A/H1N1 neuraminidase has been published recently. Using molecular dynamic simulations, it is now possible to characterize at the atomic level the mechanism that underlies the loss of binding affinity of the drugs. In this study, free-energy perturbation was used to evaluate the relative binding free energies of Tamiflu and Relenza with H274Y, N294S, and Y252H neuraminidase mutants. Our results demonstrate a remarkable correlation between theoretical and experimental data, which quantitatively confirms that the mutants are resistant to Tamiflu but are still strongly inhibited by Relenza. The simulations further reveal the key interactions that govern the affinity of the two drugs for each mutant. This information is envisioned to prove useful for the design of novel neuraminidase inhibitors and for the characterization of new potential mutants.
新型人甲型流感病毒（A/H1N1）突变株对抗病毒药物表现出耐药性。然而，它们对这些药物产生不敏感性的机制尚不完全清楚。最近已经发表了 A/H1N1 神经氨酸酶的晶体结构。现在，使用分子动力学模拟，可以在原子水平上描述药物结合亲和力丧失的机制。在这项研究中，我们使用自由能微扰来评估达菲和瑞乐沙与 H274Y、N294S 和 Y252H 神经氨酸酶突变体的相对结合自由能。我们的结果表明，理论和实验数据之间存在显著的相关性，这定量证实了突变体对达菲具有耐药性，但仍然被瑞乐沙强烈抑制。模拟进一步揭示了控制两种药物与每种突变体亲和力的关键相互作用。这些信息有望用于设计新型神经氨酸酶抑制剂和表征新的潜在突变体。
