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.

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通过衣壳“峡谷”摄动对人类鼻病毒的抑制作用：对新型苯并噻吩衍生物作用的结构性认识

多年来针对人类鼻病毒（HRV）的挑战归因于HRV血清型的多样性。尽管如此，寻找针对HRV的治疗剂的努力仍在继续。最近发现的新型苯并噻吩衍生物可抑制HRV病毒复制，从而增强了这些努力。该化合物与HRV-B14亚型结合，显示出与已知衣壳抑制剂Pleconaril类似的抑制活性。但是，这种抑制作用的分子和结构基础仍然不清楚。在这份计算机报告中，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，扭曲了其最初广泛连接的紧凑残基分布。其特点是残基间氢键较少，减少范德华相互作用，并提高残留物的柔韧性。然而，有趣的是，这种苯并噻吩衍生物的结合降低了峡谷区域周围南北壁的柔韧性，可能阻碍了HRV-B14的“呼吸运动”，因此对其产生抑制作用。原子学的见解还揭示了Tyr152对HRV-B14抑制剂结合的重要性。氨基酸与两种抑制剂的高分子间相互作用证明了这一点。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中重申了其作为替代衣壳抑制剂对普通感冒疗法的潜力。这种苯并噻吩衍生物的结合降低了峡谷区域周围南北壁的柔韧性，可能阻碍了HRV-B14的“呼吸运动”，因此对其产生抑制作用。原子学的见解还揭示了Tyr152对HRV-B14抑制剂结合的重要性。氨基酸与两种抑制剂的高分子间相互作用证明了这一点。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中重申了其作为替代衣壳抑制剂对普通感冒疗法的潜力。这种苯并噻吩衍生物的结合降低了峡谷区域周围南北壁的柔韧性，可能阻碍了HRV-B14的“呼吸运动”，因此对其产生抑制作用。原子学的见解还揭示了Tyr152对HRV-B14抑制剂结合的重要性。氨基酸与两种抑制剂的高分子间相互作用证明了这一点。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中重申了其作为替代衣壳抑制剂对普通感冒疗法的潜力。原子学的见解还揭示了Tyr152对HRV-B14抑制剂结合的重要性。氨基酸与两种抑制剂的高分子间相互作用证明了这一点。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中重申了其作为替代衣壳抑制剂对普通感冒疗法的潜力。原子学的见解还揭示了Tyr152对HRV-B14抑制剂结合的重要性。氨基酸与两种抑制剂的高分子间相互作用证明了这一点。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中重申了其作为替代衣壳抑制剂对普通感冒疗法的潜力。