Peptides and peptidomimetics are strongly re-emerging as amenable candidates in the development of therapeutic strategies against a plethora of pathologies. In particular, these molecules are extremely suitable to treat diseases in which a major role is played by protein-protein interactions (PPIs). Unlike small organic compounds, peptides display both a high degree of specificity avoiding secondary off-targets effects and a relatively low degree of toxicity. Further advantages are provided by the possibility to easily conjugate peptides to functionalized nanoparticles, so improving their delivery and cellular uptake. In many cases, such molecules need to assume a specific three-dimensional conformation that resembles the bioactive one of the endogenous ligand. To this end, chemical modifications are introduced in the polypeptide chain to constrain it in a well-defined conformation, and to improve the drug-like properties. In this context, a successful strategy for peptide/peptidomimetics design and optimization is to combine different computational approaches ranging from structural bioinformatics to atomistic simulations. Here, we review the computational tools for peptide design, highlighting their main features and differences, and discuss selected protocols, among the large number of methods available, used to assess and improve the stability of the functional folding of the peptides. Finally, we introduce the simulation techniques employed to predict the binding affinity of the designed peptides for their targets.

中文翻译：

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生物信息学和生物模拟作为肽和肽模拟物设计的工具箱：我们在哪里？


肽和肽模拟物正在强势重新出现，成为开发针对多种病理学的治疗策略的合适候选者。特别是，这些分子非常适合治疗蛋白质-蛋白质相互作用（PPI）发挥主要作用的疾病。与小型有机化合物不同，肽表现出高度的特异性，避免继发性脱靶效应，并且毒性相对较低。进一步的优点是可以轻松地将肽与功能化纳米颗粒缀合，从而改善它们的递送和细胞摄取。在许多情况下，此类分子需要呈现一种特定的三维构象，类似于内源配体的生物活性构象。为此，在多肽链中引入化学修饰，将其限制在明确的构象中，并改善药物样特性。在这种背景下，肽/肽模拟物设计和优化的成功策略是结合从结构生物信息学到原子模拟的不同计算方法。在这里，我们回顾了肽设计的计算工具，强调了它们的主要特征和差异，并讨论了在大量可用方法中用于评估和提高肽功能折叠稳定性的选定方案。最后，我们介绍了用于预测设计的肽与其靶标的结合亲和力的模拟技术。