Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, Essen 45141, Germany.
Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.
J Proteome Res. 2022 Aug 5;21(8):1829-1841. doi: 10.1021/acs.jproteome.2c00020. Epub 2022 Jun 2.
Virtual screening of protein-protein and protein-peptide interactions is a challenging task that directly impacts the processes of hit identification and hit-to-lead optimization in drug design projects involving peptide-based pharmaceuticals. Although several screening tools designed to predict the binding affinity of protein-protein complexes have been proposed, methods specifically developed to predict protein-peptide binding affinity are comparatively scarce. Frequently, predictors trained to score the affinity of small molecules are used for peptides indistinctively, despite the larger complexity and heterogeneity of interactions rendered by peptide binders. To address this issue, we introduce PPI-Affinity, a tool that leverages support vector machine (SVM) predictors of binding affinity to screen datasets of protein-protein and protein-peptide complexes, as well as to generate and rank mutants of a given structure. The performance of the SVM models was assessed on four benchmark datasets, which include protein-protein and protein-peptide binding affinity data. In addition, we evaluated our model on a set of mutants of EPI-X4, an endogenous peptide inhibitor of the chemokine receptor CXCR4, and on complexes of the serine proteases HTRA1 and HTRA3 with peptides. PPI-Affinity is freely accessible at https://protdcal.zmb.uni-due.de/PPIAffinity.
蛋白质-蛋白质和蛋白质-肽相互作用的虚拟筛选是一项具有挑战性的任务，直接影响到基于肽的药物设计项目中涉及的命中鉴定和命中到先导优化的过程。尽管已经提出了几种旨在预测蛋白质-蛋白质复合物结合亲和力的筛选工具，但专门用于预测蛋白质-肽结合亲和力的方法相对较少。通常，用于评分小分子亲和力的预测器会不加区分地用于肽，尽管肽配体的相互作用更复杂且具有更大的异质性。为了解决这个问题，我们引入了 PPI-Affinity，这是一种利用支持向量机 (SVM) 结合亲和力预测器筛选蛋白质-蛋白质和蛋白质-肽复合物数据集的工具，以及生成和对给定结构的突变体进行排序。SVM 模型的性能在四个基准数据集上进行了评估，其中包括蛋白质-蛋白质和蛋白质-肽结合亲和力数据。此外，我们还在一组 EPI-X4 的突变体（趋化因子受体 CXCR4 的内源性肽抑制剂）和丝氨酸蛋白酶 HTRA1 和 HTRA3 与肽的复合物上评估了我们的模型。PPI-Affinity 可在 https://protdcal.zmb.uni-due.de/PPIAffinity 上免费获取。
