Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.
Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.
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DOI：
10.1016/j.ebiom.2016.06.010
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Nishida N
中科院分区：
文献类型：
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作者：
Ishibashi D;Nakagaki T;Ishikawa T;Atarashi R;Watanabe K;Cruz FA;Hamada T;Nishida N
朊病毒疾病的发病机制可能是由朊蛋白的正常细胞亚型转化而来的异常朊蛋白（PrPSc）积累所致。因此，针对这些疾病的药物发现研究集中在蛋白质转化过程。我们使用了一种基于结构的药物发现算法（称为长崎大学对接引擎：NUDE），该算法在一台具有图形处理单元的密集型超级计算机上运行，以识别几种具有抗朊病毒作用的化合物。在表现出高结合分数的候选者中，化合物在体外与重组PrP表现出直接相互作用，并且在朊病毒感染的细胞中显著减少PrPSc和蛋白-侵袭体。碎片分子轨道计算表明，PrPC与蛋白质的结合主要以货车范德华力为分子间作用方式。此外，PrPSc的积累和小胶质细胞增生显着减少在治疗小鼠的大脑中，这表明候选药物提供保护朊病毒疾病，虽然需要进一步的体内试验来证实这些发现。这种基于NUDE的基于结构的正常蛋白质结构的药物发现可能有助于开发治疗其他构象障碍的药物，如阿尔茨海默病。NPR由密集型超级计算机“DEGIMA”上进行的基于结构的药物发现（SBDD）算法进行搜索。使用表面等离子体共振分析和热位移测定，NPR与PrPC结合。NPR与PrPC通过货车范德华相互作用结合，使用片段分子轨道计算。NPRs抑制PrPSc水平和持续朊病毒感染细胞中的侵袭体。NPR抑制朊病毒感染小鼠脑中PrPSc水平和小胶质细胞活化使用SBDD的计算机药物发现使得能够开发用于朊病毒疾病的可用治疗剂。目前尚无有效的朊病毒病治疗剂。在这篇文章中，我们描述了使用新的筛选系统来发现抗朊病毒疾病的药物。在这个系统中，我们进行对接模拟使用原始的计算系统，称为DEGIMA超级计算机，并从众多的化合物库中搜索候选化合物作为抗朊病毒药物。这些化合物直接与重组朊病毒蛋白相互作用，并显著减少朊病毒感染细胞和患病小鼠脑中的异常形式朊病毒蛋白。这一药物发现可能有助于治疗构象障碍的治疗开发。
The accumulation of abnormal prion protein (PrPSc) converted from the normal cellular isoform of PrP (PrPC) is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE) that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects. Among the candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrPSc and protein-aggresomes in the prion-infected cells. The fragment molecular orbital calculation showed that the van der Waals interaction played a key role in PrPC binding as the intermolecular interaction mode. Furthermore, PrPSc accumulation and microgliosis were significantly reduced in the brains of treated mice, suggesting that the drug candidates provided protection from prion disease, although further in vivo tests are needed to confirm these findings. This NUDE-based structure-based drug discovery for normal protein structures is likely useful for the development of drugs to treat other conformational disorders, such as Alzheimer's disease. NPRs are hunted by a structure-based drug discovery (SBDD) algorithm carried on an intensive supercomputer “DEGIMA”. NPRs bind to PrPC using surface plasmon resonance analysis and thermal shift assay. NPRs bind to PrPC by van der Waals interaction using the fragment molecular orbital calculation. NPRs suppress PrPSc levels and aggresomes in persistently prion-infected cells. NPRs inhibit PrPSc levels and microglia activation in prion-infected mice brain. In silico drug discovery using SBDD enable to develop the available therapeutic agents for prion disease. None of effective and efficient therapeutic agents for prion disease is available. In this manuscript, we describe the drug discovery against prion disease using novel screening system. In this system, we performed docking simulation using original calculation system, termed DEGIMA supercomputer, and searched candidate compounds as anti-prion drug from among the many chemical compounds library. The compounds directly interacted with recombinant prion protein, and drastically reduced abnormal form prion protein in the prion-infected cells and the brain of illness mice. This drug discovery may be useful for the therapeutic development to cure conformational disorders.