PDF(Pubmed)
Abstract：
Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand-enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.
摘要：
猴痘是热带和亚热带地区严重的公共卫生问题。靶向猴痘蛋白的抗病毒药物可能会导致更有效和高效的治疗。F13蛋白对于猴痘病毒的生长和成熟至关重要。F13抑制可能是猴痘的可行治疗靶标。用于开发抗病毒药物的基于芯片片段的药物发现方法可以提供新的治疗选择。在这项研究中,我们基于tecovirimat产生了800种化合物，一种FDA批准的药物，在纳摩尔量时对猴痘有效。评估这些化合物以基于结合亲和力和药理学特征鉴定最有希望的片段。来自化学筛选的最高命中物被停靠在F13蛋白的活性位点中。对来自分子对接的前两个可能的新候选物进行分子动力学模拟。配体-酶相互作用分析表明，C2配体的结合自由能低于标准配体tecovirimat。水桥,在其他互动中，被证明可以稳定C2分子。在C2结合时F13蛋白的构象转换和二级结构变化显示出更天然的蛋白质三维折叠。药理特性的预测表明，化合物C2可能有望作为猴痘热的候选药物。然而,需要额外的体外和体内测试进行验证。
