Mimicking bioactive conformations of peptide segments involved in the formation of protein-protein interfaces with small molecules is thought to represent a promising strategy for the design of protein-protein interaction (PPI) inhibitors. For compound design, the use of three-dimensional (3D) scaffolds rich in sp3-centers makes it possible to precisely mimic bioactive peptide conformations. Herein, we introduce DeepCubist, a molecular generator for designing peptidomimetics based on 3D scaffolds. Firstly, enumerated 3D scaffolds are superposed on a target peptide conformation to identify a preferred template structure for designing peptidomimetics. Secondly, heteroatoms and unsaturated bonds are introduced into the template via a deep generative model to produce candidate compounds. DeepCubist was applied to design peptidomimetics of exemplary peptide turn, helix, and loop structures in pharmaceutical targets engaging in PPIs.

模拟参与蛋白质-蛋白质界面形成的肽片段的生物活性构象与小分子被认为是设计蛋白质-蛋白质相互作用 (PPI) 抑制剂的有前途的策略。对于化合物设计，使用富含 sp3 中心的三维 (3D) 支架可以精确模拟生物活性肽构象。在此，我们介绍了 DeepCubist，一种用于设计基于 3D 支架的拟肽的分子生成器。首先，将枚举的 3D 支架叠加在目标肽构象上，以确定用于设计拟肽的首选模板结构。其次，通过深度生成模型将杂原子和不饱和键引入模板，生成候选化合物。