Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus.
Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus.
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DOI：
10.3390/v15020570
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发表时间：
2023-02-19
期刊：
影响因子：
--
通讯作者：
Ji XY
中科院分区：
文献类型：
--
作者：
Ali Y;Imtiaz H;Tahir MM;Gul F;Saddozai UAK;Ur Rehman A;Ren ZG;Khattak S;Ji XY
猴痘在热带和亚热带地区是一个严重的公共卫生问题。针对猴痘蛋白的抗病毒药物可能会带来更有效的治疗。F13蛋白对猴痘病毒的生长和成熟是必不可少的。抑制F13可能是猴痘的一个可行的治疗靶点。基于电子片段开发抗病毒药物的药物发现方法可能提供新的治疗选择。在这项研究中，我们基于Tecovirimat产生了800种化合物，Tecovirimat是FDA批准的一种治疗猴痘的纳摩尔量有效的药物。根据结合亲和力和药理学特征对这些化合物进行评估，以确定最有希望的片段。化学筛选的最高命中率被对接到F13蛋白的活性部位。对来自分子对接的前两个可能的新候选者进行了分子动力学模拟。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。在其他相互作用中，水桥被证明稳定了C2分子。当C2结合时，F13蛋白的构象转变和二级结构变化表明该蛋白更具天然的三维折叠。药理性质预测显示，化合物C2有望成为治疗猴痘热的候选药物。然而，还需要额外的体外和体内测试来进行验证。
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.
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影响因子：
8
作者：
COLOVOS, C;YEATES, TO
通讯作者：
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影响因子：
64.8
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2.9
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影响因子：
4.6
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