Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India.
Appl Biochem Biotechnol. 2012 May;167(2):237-49. doi: 10.1007/s12010-012-9687-7. Epub 2012 Apr 28.
Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (<1%) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems.
奥司他韦（达菲）是治疗流感病毒感染患者的首选抗病毒药物。该药物的主要靶标是病毒表面糖蛋白神经氨酸酶（NA），它有助于新生病毒的释放，从而传播感染。直到最近，在循环病毒中仅检测到低流行率的神经氨酸酶抑制剂（NAI）耐药性（<1%）。然而，已有报道称，大量 A（H1N1）流感株存在对 NAI、奥司他韦高度耐药的 H274Y 神经氨酸酶突变。在这项研究中，我们通过分子对接和分子动力学模拟方法强调了点突变诱导的 H1N1 亚型神经氨酸酶对奥司他韦耐药性的影响。我们的结果表明，野生型 NA 可能更需要与奥司他韦结合，因为其氢键数量最少、灵活性最高且结合亲和力最大，而突变型 NA 则不是。这项研究阐明了耐药性突变对生物系统中大型功能重要整体运动的可能影响。
