Department of Neurobiology, Scuola Internazionale Superiore di Studi Avanzati-International School for Advanced Studies, Trieste, Italy.
PLoS One. 2010 Feb 16;5(2):e9234. doi: 10.1371/journal.pone.0009234.
The action of dopamine on the aggregation of the unstructured alpha-synuclein (alpha-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit alpha-syn aggregation by non-covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of alpha-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non-covalently to alpha-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein.
多巴胺对无规卷曲的α-突触核蛋白（α-syn）的聚集作用可能与帕金森病的发病机制有关。多巴胺及其氧化衍生物可能通过非共价结合抑制α-syn 的聚集。利用这一事实，我们采用了综合计算和实验的方法来寻找可能调节α-syn 纤维化的替代配体。从已建立的文库中筛选出与多巴胺在结构和静电上相似的配体。从相似性排列的配体列表中选择了五种类似物进行体外实验。分子动力学模拟表明，它们与多巴胺一样，非共价结合到α-syn 上，尽管比多巴胺弱得多，但它们具有一些相同的结合特性。对这五种多巴胺类似物进行了体外纤维化测定。与我们的预测一致，原子力和透射电子显微镜的分析表明，所有选定的配体都影响了聚合过程，尽管程度比用作对照配体的多巴胺要小得多。这里提出的计算/体外方法可能是一种识别干扰无规卷曲蛋白纤维化等复杂过程的配体的策略。
