Fernando Sandun, Fernando Teshan
Biological and Agricultural Engineering Department, TAMU, 303C, Scoates Hall, 2117, College Station, TX, 77843, USA.
BMC Res Notes. 2017 Jul 28;10(1):354. doi: 10.1186/s13104-017-2685-7.
An approach to inhibiting enveloped flaviviruses is to deter the ability of the envelope protein(s) binding onto glycoproteins. In previous work, using a small ~100-amino acid homology model of Zika virus envelope protein (ZVEP), we proved the susceptibility of Zika virus to inhibition. In this work, we verify the efficacy of the homology model based antiviral search method using a larger protein (>400 amino acids) and comparing the results with the experimentally determined one (PDB ID:5IRE).
By examining how glycan molecules, small-molecule probes and screened ligands that have a high affinity to ZVEP, we report the mechanics of ZVEP to inhibition via allosteric blockage of the glycan-binding domain while proposing even more possibly potent inhibitors. The small molecular probes based study using the homology model and subsequently verified using actual experimental structure, 5IRE, revealed that ZVEP is druggable. A pharmacophore analysis followed by screening showed at least four ligands that allosterically binds to the glycan binding domain constituted by residues VAL 153 and ASN 154 in 5IRE. Based on further selection criteria ZINC40621658 was identified to have high potential to be a strong antiviral candidate for Zika virus inhibition.
抑制包膜黄病毒的一种方法是阻止包膜蛋白与糖蛋白结合的能力。在之前的工作中，我们使用寨卡病毒包膜蛋白（ZVEP）约100个氨基酸的小同源模型，证明了寨卡病毒对抑制作用的敏感性。在这项工作中，我们使用更大的蛋白质（>400个氨基酸）验证基于同源模型的抗病毒搜索方法的有效性，并将结果与实验测定的结果（PDB ID：5IRE）进行比较。
通过研究与ZVEP具有高亲和力的聚糖分子、小分子探针和筛选出的配体，我们报告了ZVEP通过变构阻断聚糖结合域来实现抑制的机制，同时提出了更具潜力的抑制剂。基于同源模型并随后使用实际实验结构5IRE进行验证的小分子探针研究表明，ZVEP是可成药的。药效团分析及随后的筛选显示，至少有四种配体与由5IRE中VAL 153和ASN 154残基构成的聚糖结合域变构结合。基于进一步的筛选标准，确定ZINC40621658具有很高的潜力成为寨卡病毒抑制的强效抗病毒候选物。
