Small heterocyclic molecules such as piperazine are potential pharmacotherapeutic agents and binding of these molecules to the hydrophobic pocket of capsid protein (CP) offers a new perspective for therapeutic intervention. Here, we report the crystal structure of CP from Aura virus (AVCP) in complex with piperazine at 2.2 Å resolution. Piperazine binds to the conserved hydrophobic pocket of CP where dioxane based antivirals bind. Comparative structural studies of the piperazine-bound AVCP structure with the apo, active and dioxane-bound AVCP structures provide insights into the conformational variations in the pocket. Additionally, the molecular docking studies showed that piperazine binds into the hydrophobic pocket of Chikungunya virus CP (CVCP) with more affinity than with AVCP. Furthermore, the antiviral activity of piperazine against Chikungunya virus (CHIKV) was investigated by plaque reduction and immunofluorescence assays. The AVCP-piperazine complex may serve as a lead scaffold for structure-based design of piperazine derivatives as alphaviral inhibitors. The antiviral properties of piperazine provide its usefulness for further investigations towards the development of piperazine based anti-alphaviral drugs.

小杂环分子（例如哌嗪）是潜在的药物治疗剂，这些分子与衣壳蛋白（CP）疏水口袋的结合为治疗干预提供了新的视角。在这里，我们报告了与2.2分辨率的哌嗪复合的光环病毒（AVCP）中CP的晶体结构。哌嗪结合CP的保守的疏水口袋，其中基于二恶烷的抗病毒剂结合。哌嗪结合的AVCP结构与载脂蛋白，活性化合物和二恶烷结合的AVCP结构的比较结构研究为洞中的构象变化提供了见识。此外，分子对接研究表明，哌嗪与基孔肯雅病毒CP（CVCP）的疏水口袋比与AVCP的亲和力更高。此外，通过噬斑减少和免疫荧光分析研究了哌嗪对基孔肯雅病毒（CHIKV）的抗病毒活性。AVCP-哌嗪复合物可用作铅骨架，用于哌嗪衍生物作为α病毒抑制剂的基于结构的设计。哌嗪的抗病毒特性为进一步开发基于哌嗪的抗α病毒药物提供了有用的信息。