基于虚拟筛选与分子动力学模拟探究轮状病毒抑制剂研发

Exploring potent inhibitors of rotavirus via Virtual Screening and Molecular Dynamics Simulation

目的:探究人优势轮状病毒毒株(Rotaviruses,RVs)VP8;是否存在与脂肪酸保守性结合的位点,从中筛选出与VP8;靶点特异性结合的分子。方法:应用分子对接的方法,搜寻VP8;与脂肪酸分子结合的可能位点,并利用虚拟筛选从包含7655个化合物的数据库中针对潜在位点进行对接,然后对得分高的蛋白配体复合物进行分子动力学(MD)模拟。结果:分子对接发现脂肪酸酸结合于VP8表面的似峡谷的口袋,脂肪酸与预测的口袋之间形成了较强的相互作用;虚拟筛选打分与MD模拟的参数证实了Doxorubicin-Semiquinone、 ZINC000004216238VP8结合的稳定性。结论:人优势流行株轮状病毒蛋白VP8;与脂肪酸分子结合具有保守性,Doxorubicin-Semiquinone、ZINC000004216238可以作为人轮状病毒的潜在抑制剂的分子骨架。

Objective To explore whether prevalent human rotavirus strains have conservative binding sites anchoring fatty acids and to screen out the potential compounds for rotavirus VP8;binding.Methods The potential binding sites of VP8;for fatty acid were searched by Molecular Docking,and the potential binding sites were docked from a database containing 7655 compounds by Virtual Screening method.Then Molecular Dynamics Simulation was performed on the protein-ligand complexes with high scores.Results Molecular Docking revealed that the fatty acid was bound to the canyon-like pocket of VP8;,with a strong interaction being formed between the fatty acid and the predicted pocket.Parameters from the Virtual Screening scores and MD simulations confirmed the stability of the binding of Doxorubicin-Semiquinone and ZINC000004216238 to VP8;.Conclusion The binding of rotavirus protein VP8;to fatty acid molecules is conservative in the dominant human epidemic strain.Results further show that Doxorubicin-Semiquinone and ZINC000004216238 can be used as molecular scaffolds of potential inhibitors targeting human rotavirus.