Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity
Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity
复制标题
DOI：
10.1128/aac.01112-08
复制
发表时间：
2009-02-01
影响因子：
4.9
通讯作者：
Kuwata, Kazuo
中科院分区：
文献类型：
--
作者：
Hosokawa-Muto, Junji;Kamatari, Yuji O.;Kuwata, Kazuo
传染性海绵状脑病与PrPC蛋白的构象转换有关。这一过程可以通过使用被鉴定为化学伴侣的特定配体稳定PrPC构象来中断。为了发现这样的化合物，我们使用了一种基于PrPC的核磁共振结构的电子屏幕。结合使用福冈-1菌株感染的小鼠神经元细胞株，在10muM的复合浓度下进行体外筛选，并进行表面等离子共振。最初，我们根据计算的对接能选择了590个化合物，最终发现了24个有效的反病毒化合物，它们的化学结构相当多样化。表面等离子体共振研究表明，化合物与PrPC的结合亲和力与化合物的抗PrPC活性大致相关，表明鉴定与PrPC结构结合并稳定其结构的化学伴侣是发现抗PrPC药物的有效策略之一。然而，一些化合物对PrPC具有低亲和力的反病毒活性，这表明其机制涉及额外的调节因子。我们将化合物大致分为五类：(I)结合有效，(Ii)低结合有效，(Iii)结合无效，(Iv)低结合无效，(V)加速。总之，我们发现了一系列化合物，其中许多能够调节致病转化反应。对这些不同的化合物进行适当的分类，将有助于发现抗病毒药物，并有助于阐明致病转化机制。
Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrPC) to the scrapie form. This process could be disrupted by stabilizing the PrPC conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrPC. In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 mu M and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient antiprion compounds, whose chemical structures are quite diverse. Surface plasmon resonance studies showed that the binding affinities of compounds for PrPC roughly correlated with the compounds' antiprion activities, indicating that the identification of chemical chaperones that bind to the PrPC structure and stabilize it is one efficient strategy for antiprion drug discovery. However, some compounds possessed antiprion activities with low affinities for PrPC, indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective, (ii) low binding and effective, (iii) binding and not effective, (iv) low binding and not effective, and (v) acceleration. In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate antiprion drug discovery and help to elucidate the pathogenic conversion mechanism.