Institute for Computational Science and Technology, 6 Quarter, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam.
J Chem Inf Model. 2010 Dec 27;50(12):2236-47. doi: 10.1021/ci100346s. Epub 2010 Nov 23.
Since March 2009, the rapid spread of infection during the recent A/H1N1 swine flu pandemic has raised concerns of a far more dangerous outcome should this virus become resistant to current drug therapies. Currently oseltamivir (tamiflu) is intensively used for the treatment of influenza and is reported effective for 2009 A/H1N1 virus. However, as this virus is evolving fast, some drug-resistant strains are emerging. Therefore, it is critical to seek alternative treatments and identify roots of the drug resistance. In this paper, we use the steered molecular dynamics (SMD) approach to estimate the binding affinity of ligands to the glycoprotein neuraminidase. Our idea is based on the hypothesis that the larger is the force needed to unbind a ligand from a receptor the higher its binding affinity. Using all-atom models with Gromos force field 43a1 and explicit water, we have studied the binding ability of 32 ligands to glycoprotein neuraminidase from swine flu virus A/H1N1. The electrostatic interaction is shown to play a more important role in binding affinity than the van der Waals one. We have found that four ligands 141562, 5069, 46080, and 117079 from the NSC set are the most promising candidates to cope with this virus, while peramivir, oseltamivir, and zanamivir are ranked 8, 11, and 20. The observation that these four ligands are better than existing commercial drugs has been also confirmed by our results on the binding free energies obtained by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. Our prediction may be useful for the therapeutic application.
自 2009 年 3 月以来，近期 A/H1N1 猪流感的迅速传播引起了人们的担忧，如果这种病毒对当前的药物疗法产生抗药性，可能会导致更危险的后果。目前，奥司他韦（达菲）被广泛用于治疗流感，并被报道对 2009 年 A/H1N1 病毒有效。然而，由于这种病毒进化迅速，一些耐药株正在出现。因此，寻找替代疗法和确定耐药根源至关重要。在本文中，我们使用定向分子动力学（SMD）方法来估计配体与糖蛋白神经氨酸酶的结合亲和力。我们的想法基于这样的假设，即从受体上解吸配体所需的力越大，其结合亲和力就越高。我们使用全原子模型和 Gromos 力场 43a1 以及显式水，研究了 32 种配体与猪流感病毒 A/H1N1 的糖蛋白神经氨酸酶的结合能力。结果表明，静电相互作用比范德华相互作用在结合亲和力中起着更重要的作用。我们发现，来自 NSC 集的四种配体 141562、5069、46080 和 117079 是应对这种病毒最有前途的候选药物，而帕拉米韦、奥司他韦和扎那米韦的排名分别为 8、11 和 20。通过分子力学-泊松-玻尔兹曼表面积（MM-PBSA）方法获得的结合自由能的结果也证实了这四种配体比现有的商业药物更好的观察结果。我们的预测可能对治疗应用有用。
