Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Cell Biochem Biophys. 2020 Mar;78(1):3-13. doi: 10.1007/s12013-019-00896-z. Epub 2019 Dec 13.
The challenge in targeting human rhinoviruses (HRV) over the years has been attributed to the wide variety in HRV serotypes. Nonetheless, the search for therapeutic agents against HRV continues unabated. These efforts have been augmented by the recent discovery of the novel benzothiophene derivative shown to inhibit HRV viral replication. Bound to subtype HRV-B14, the compound showed similar inhibitory activity as Pleconaril, a known capsid inhibitor. However, the molecular and structural basis of this inhibition remains unclear. In this in silico report, residue interaction network analysis revealed that the binding of the benzothiophene derivative into the "canyon" region of the active site of HRV-B14 distorts its initially extensively networked and compact residue profile. This was characterized by fewer inter-residue hydrogen bonds, reduced van der Waals interactions, and increased residue flexibility. Interestingly, however, the binding of this benzothiophene derivative decreased the flexibility of the north-south wall around the canyon region possibly impeding the "breathing motion" of HRV-B14, hence its inhibition. Atomistic insights also revealed the cruciality of Tyr152 toward inhibitor binding at HRV-B14. This was justified by the amino acid's high intermolecular interaction with both inhibitors. Findings provide important structural insights in the inhibitory activity the novel benzothiophene derivative, and reaffirm its promising potential as an alternative capsid inhibitor toward common cold therapy upon further experimental validation.
多年来，靶向人类鼻病毒（HRV）的挑战归因于 HRV 血清型的多样性。尽管如此，针对 HRV 的治疗剂的研究仍在继续。最近发现了一种新型苯并噻吩衍生物，该衍生物被证明可以抑制 HRV 病毒复制，这也增强了这些努力。该化合物与亚型 HRV-B14 结合，显示出与已知衣壳抑制剂 Pleconaril 相似的抑制活性。然而，这种抑制的分子和结构基础仍不清楚。在本计算报告中，残基相互作用网络分析表明，苯并噻吩衍生物结合到 HRV-B14 活性位点的“峡谷”区域会扭曲其最初广泛连接且紧凑的残基图谱。这表现为氢键减少、范德华相互作用减少和残基柔韧性增加。有趣的是，然而，这种苯并噻吩衍生物的结合降低了峡谷区域周围的南北壁的柔韧性，可能会阻碍 HRV-B14 的“呼吸运动”，从而抑制其复制。原子洞察还揭示了 Tyr152 对 HRV-B14 抑制剂结合的重要性。这是由该氨基酸与两种抑制剂都具有很高的分子间相互作用所证明的。这些发现为新型苯并噻吩衍生物的抑制活性提供了重要的结构见解，并在进一步的实验验证后，再次证实了其作为普通感冒治疗的替代衣壳抑制剂的潜在价值。
