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首页> 外文期刊>Journal of Computer-Aided Molecular Design >In silico identification and in vitro antiviral validation of potential inhibitors against Chikungunya virus
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In silico identification and in vitro antiviral validation of potential inhibitors against Chikungunya virus

机译：基孔肯雅病毒潜在抑制剂的计算机鉴定和体外抗病毒验证

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Abstract The Chikungunya virus (CHIKV) has become endemic in the Africa, Asia and Indian subcontinent, with its continuous re-emergence causing a significant public health crisis. The unavailability of specific antivirals and vaccines against the virus has highlighted an urgent need for novel therapeutics. In the present study, we have identified small molecule inhibitors targeting the envelope proteins of the CHIKV to interfere with the fusion process, eventually inhibiting the cell entry of the virus particles. We employed high throughput computational screening of large datasets against two different binding sites in the E1–E2 dimer to identify potential candidate inhibitors. Among them, four high affinity inhibitors were selected to confirm their anti-CHIKV activity in the in vitro assay. Quercetin derivatives, Taxifolin and Rutin, binds to the E1–E2 dimer at different sites and display inhibition of CHIKV infection with EC50 values 3.6 μM and 87.67 μM, respectively. Another potential inhibitor with ID ChemDiv 8015-3006 binds at both the target sites and shows anti-CHIKV activity at EC50 = 41 μM. The results show dose-dependent inhibitory effects of Taxifolin, Rutin and ChemDiv 8015-3006 against the CHIKV with minimal cytotoxicity. In addition, molecular dynamics studies revealed the structural stability of these inhibitors at their respective binding sites in the E1–E2 protein. In conclusion, our study reports Taxifolin, Rutin and ChemDiv 8015-3006 as potential inhibitors of the CHIKV entry. Also, this study suggests a few potential candidate inhibitors which could serve as a template to design envelope protein specific CHIKV entry inhibitors.
机译：摘要 基孔肯雅热病毒（CHIKV）在非洲、亚洲和印度次大陆流行，其不断卷土重来，引发了严重的公共卫生危机。针对该病毒的特定抗病毒药物和疫苗的缺乏凸显了对新型疗法的迫切需求。在本研究中，我们确定了靶向CHIKV包膜蛋白的小分子抑制剂，以干扰融合过程，最终抑制病毒颗粒进入细胞。我们针对 E1-E2 二聚体中的两个不同结合位点对大型数据集进行了高通量计算筛选，以鉴定潜在的候选抑制剂。其中，筛选出4种高亲和力抑制剂，在体外试验中证实了其抗CHIKV活性。槲皮素衍生物 Taxifolin 和 Rutin，在不同位点与 E1-E2 二聚体结合，并显示出对 CHIKV 感染的抑制作用，EC50 值分别为 3.6 μM 和 87.67 μM。另一种具有 ID ChemDiv 8015-3006 的潜在抑制剂在两个靶位点结合，并在 EC50 = 41 μM 时显示出抗 CHIKV 活性。结果显示，Taxifolin、Rutin和ChemDiv 8015-3006对CHIKV具有剂量依赖性抑制作用，细胞毒性最小。此外，分子动力学研究揭示了这些抑制剂在E1-E2蛋白中各自结合位点的结构稳定性。总之，我们的研究报告了 Taxifolin、Rutin 和 ChemDiv 8015-3006 作为 CHIKV 进入的潜在抑制剂。此外，这项研究提出了一些潜在的候选抑制剂，可以作为设计包膜蛋白特异性CHIKV进入抑制剂的模板。

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