Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Department of Physics, University of Trento, Trento, Italy.
Curr Opin Pharmacol. 2019 Feb;44:39-45. doi: 10.1016/j.coph.2019.03.015. Epub 2019 May 3.
A number of previous successful attempts in the search for therapeutics for a variety of human pathologies highlight the importance of computational technologies in the drug discovery pipeline. This approach, often referred to as computer-aided drug design, is unfortunately inapplicable when the precise information regarding the three-dimensional structure of disease-associated proteins or the mechanism by which they are altered to generate misfolded isoforms are missing. A typical example is represented by prion diseases, fatal pathologies of the nervous system characterized by the conformational conversion of a physiological protein called PrP into a misfolded and infectious isoform referred to as PrP. Missing information regarding the atomic structure of PrP as well as the mechanism of templated conversion of PrP has severely halted the discovery of effective therapies for prion diseases. In this manuscript, we review emerging opportunities to apply computer-aided techniques to target PrP, PrP or to design inhibitors of prion replication, and discuss how these fast-evolving technologies could lay the groundwork for the application of entirely novel rational drug design schemes for these devastating pathologies.
许多先前在寻找治疗各种人类疾病的疗法方面的成功尝试突出了计算技术在药物发现管道中的重要性。当关于与疾病相关的蛋白质的三维结构的精确信息或它们发生变化以产生错误折叠异构体的机制缺失时，这种方法通常被称为计算机辅助药物设计，但不幸的是，这种方法并不适用。朊病毒病就是一个典型的例子，朊病毒病是一种致命的神经系统疾病，其特征是生理蛋白 PrP 发生构象转换，形成错误折叠和具有感染性的异构体，称为 PrP。由于缺乏关于 PrP 的原子结构以及 PrP 模板转换机制的信息，严重阻碍了针对朊病毒病的有效疗法的发现。在本文中，我们回顾了应用计算机辅助技术靶向 PrP、PrP 或设计抑制朊病毒复制的抑制剂的新机会，并讨论了这些快速发展的技术如何为这些破坏性疾病的全新合理药物设计方案的应用奠定基础。
