a Department of Physics , Bharathiar University , Coimbatore , India.
J Biomol Struct Dyn. 2018 Dec;36(16):4255-4269. doi: 10.1080/07391102.2017.1413422. Epub 2017 Dec 20.
Oseltamivir (Tamiflu) is the most accepted antiviral drug that targets the neuraminidase (NA) protein to inhibit the viral release from the host cell. Few H1N1 influenza strains with the H274Y mutation creates drug resistance to oseltamivir. In this study, we report that flavonoid cyanidin-3-sambubiocide (C3S) compound acts as a potential inhibitor against H274Y mutation. The drug resistance mechanism and inhibitory activity of C3S and oseltamivir against wild-type (WT) and H274Y mutant-type (MT) have been studied and compared based on the results of molecular docking, molecular dynamics, and quantum chemical methods. Oseltamivir has been found less binding affinity with MT. C3S has more binding affinity with WT and MT proteins. From the dynamical study, the 150th loop of the MT protein has found more deformation than WT. A single H274Y mutation induces the conformational changes in the 150th loop which leads to produce more resistance to oseltamivir. The 150th cavity is more attractive target for C3S to stop the conformational changes in the MT, than 430th cavity of NA protein. The C3S is stabilized with MT by more number of hydrogen bonds than oseltamivir. The electrostatic interaction energy shows a stronger C3S binding with MT and this compound may be more effective against oseltamivir-resistant virus strains.
奥司他韦（达菲）是最被接受的抗病毒药物，它靶向神经氨酸酶（NA）蛋白，以抑制病毒从宿主细胞中释放。少数具有 H274Y 突变的 H1N1 流感株对奥司他韦产生耐药性。在这项研究中，我们报告了类黄酮矢车菊素-3-桑布比定（C3S）化合物作为一种潜在的抑制剂对抗 H274Y 突变。基于分子对接、分子动力学和量子化学方法的结果，研究并比较了 C3S 和奥司他韦对野生型（WT）和 H274Y 突变型（MT）的耐药机制和抑制活性。奥司他韦与 MT 的结合亲和力较低。C3S 与 WT 和 MT 蛋白的结合亲和力更强。从动力学研究中，发现 MT 蛋白的第 150 个环发生了更多的变形，而 WT 蛋白则没有。单个 H274Y 突变诱导 150 号环发生构象变化，从而产生对奥司他韦更强的耐药性。第 150 号腔隙是 C3S 阻止 MT 构象变化的更具吸引力的靶标，而不是 NA 蛋白的第 430 号腔隙。C3S 通过比奥司他韦更多的氢键与 MT 稳定结合。静电相互作用能显示 C3S 与 MT 的结合更强，该化合物可能对奥司他韦耐药的病毒株更有效。
