Center of Bioinformatics (COBI), School of Life Science and Technology, University of Electronic Science and Technology of China (UESTC), Chengdu 610054, China.
Curr Med Chem. 2013;20(15):1985-96. doi: 10.2174/0929867311320150005.
The recent focus on protein-protein interaction networks has increasingly been shifted towards the disruption of protein complexes, which either are mediated by the binding of a globular domain in one protein to a short peptide stretch in another, or involve flat, large, and hydrophobic interfaces that classical small-molecule agents are not always ideally suited. Rational design of therapeutic peptides with high affinity targeting such interactions has emerged as a new and promising tool in discovery of potential drug candidates against associated diseases. The design is commonly based on bioinformatics methods or molecular modeling techniques, indirectly exploiting structure-activity relationship at the level of peptide sequence or directly deriving lead entities from protein complex architecture. Here, a newly rising subfield called computational peptidology that focuses on the use of computational and theoretical approaches to treat peptide-related problems is comprehensively reviewed on the design and discovery of peptide agents targeting protein-protein interactions. We address a systematic discussion on several representative cases in which the computational peptidology is successfully employed to develop peptide therapeutics. Besides, some problems and pitfalls accompanied with the current use of computational methods in peptide modeling and design are also present.
最近，人们越来越关注蛋白质-蛋白质相互作用网络，研究重点逐渐转向蛋白质复合物的破坏，这些复合物要么是由一个蛋白质中的球形结构域与另一个蛋白质中的短肽片段结合介导，要么涉及平坦、大而疏水的界面，而经典的小分子药物并不总是非常适合这种界面。针对这些相互作用，设计具有高亲和力的治疗性肽已成为发现针对相关疾病的潜在药物候选物的一种新的有前途的工具。这种设计通常基于生物信息学方法或分子建模技术，间接利用肽序列水平的结构-活性关系，或直接从蛋白质复合物结构中得出先导实体。在这里，我们全面回顾了计算肽学这一新兴的子领域，该领域专注于使用计算和理论方法来解决与肽相关的问题，特别是在设计和发现针对蛋白质-蛋白质相互作用的肽类药物方面。我们讨论了几个有代表性的案例，其中计算肽学成功地被用于开发肽类疗法。此外，还存在一些与当前在肽建模和设计中使用计算方法相关的问题和陷阱。
