Department of Pharmacy, University "G d'Annunzio" of Chieti-Pescara, Chieti, Italy.
Molecular Discovery Limited, Middlesex, London, UK.
J Comput Aided Mol Des. 2021 Jun;35(6):751-770. doi: 10.1007/s10822-021-00393-7. Epub 2021 Jun 10.
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.
设计了一个多层次的计算工作流程，以鉴定人类朊病毒蛋白 E200K 致病性突变体表面的可成药结合位点，并研究小分子在抑制该蛋白早期聚集方面的结合效果。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，从而确定 PrP-E200K 表面上可能的结合区域。然后，将这些结构数据用于驱动基于结构的虚拟筛选和基于片段的方法，以寻找 PrP-E200K 的小分子结合物。鉴定了六种有前途的化合物，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之间的分子静电势相似性的分析表明，它们具有作为基于电荷的 PrP-E200K 早期聚集抑制剂的潜在活性。
