D'Annessa Ilda, Di Leva Francesco Saverio, La Teana Anna, Novellino Ettore, Limongelli Vittorio, Di Marino Daniele
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy.
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Front Mol Biosci. 2020 May 5;7:66. doi: 10.3389/fmolb.2020.00066. eCollection 2020.
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.
肽和肽模拟物作为针对多种病症的治疗策略中合适的候选物，正强势再度兴起。特别是，这些分子极其适合治疗由蛋白质-蛋白质相互作用（PPI）起主要作用的疾病。与小分子有机化合物不同，肽既具有高度特异性，可避免次要的脱靶效应，又具有相对较低的毒性。肽还具有其他优势，比如可以轻松地将其与功能化纳米颗粒偶联，从而改善其递送和细胞摄取。在许多情况下，此类分子需要呈现出类似于内源性配体生物活性构象的特定三维构象。为此，在多肽链中引入化学修饰，以将其限制在明确的构象中，并改善类药物性质。在此背景下，肽/肽模拟物设计与优化的一个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。在此，我们综述肽设计的计算工具，突出其主要特点和差异，并讨论在大量可用方法中用于评估和改善肽功能折叠稳定性的选定方案。最后，我们介绍用于预测设计肽与其靶标的结合亲和力的模拟技术。
