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Hampering the early aggregation of PrP-E200K protein by charge-based inhibitors: a computational study
Journal of Computer-Aided Molecular Design ( IF 3.5 ) Pub Date : 2021-06-10 , DOI: 10.1007/s10822-021-00393-7
Mariangela Agamennone 1 , Loriano Storchi 1, 2 , Alessandro Marrone 1 , Roberto Paciotti 1
Affiliation  

A multilayered computational workflow was designed to identify a druggable binding site on the surface of the E200K pathogenic mutant of the human prion protein, and to investigate the effect of the binding of small molecules in the inhibition of the early aggregation of this protein. At this purpose, we developed an efficient computational tool to scan the molecular interaction properties of a whole MD trajectory, thus leading to the characterization of plausible binding regions on the surface of PrP-E200K. These structural data were then employed to drive structure-based virtual screening and fragment-based approaches to the seeking of small molecular binders of the PrP-E200K. Six promising compounds were identified, and their binding stabilities were assessed by MD simulations. Therefore, analyses of the molecular electrostatic potential similarity between the bound complexes and unbound protein evidenced their potential activity as charged-based inhibitors of the PrP-E200K early aggregation.



中文翻译:

基于电荷的抑制剂阻碍 PrP-E200K 蛋白的早期聚集:一项计算研究

设计了多层计算工作流程来识别人朊病毒蛋白E200K致病突变体表面上的可药物结合位点,并研究小分子结合在抑制该蛋白早期聚集中的作用。为此,我们开发了一种有效的计算工具来扫描整个 MD 轨迹的分子相互作用特性,从而对 PrP-E200K 表面上可能的结合区域进行表征。然后利用这些结构数据来驱动基于结构的虚拟筛选和基于片段的方法来寻找 PrP-E200K 的小分子结合物。鉴定出了六种有前景的化合物,并通过 MD 模拟评估了它们的结合稳定性。因此,对结合复合物和未结合蛋白质之间分子静电势相似性的分析证明了它们作为 PrP-E200K 早期聚集的基于电荷的抑制剂的潜在活性。

更新日期:2021-06-10
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