面向靶蛋白降解的SE(3)等变三元复合物预测
SE(3)-equivariant ternary complex prediction towards target protein degradation.
作者信息
Xue Fanglei, Zhang Meihan, Li Shuqi, Gao Xinyu, Wohlschlegel James A, Huang Wenbing, Yang Yi, Deng Weixian
机构信息
ReLER Lab, AAII, University of Technology Sydney, Sydney, NSW, 2007, Australia.
College of Life Sciences, Nankai University, Tianjin, China.
出版信息
Nat Commun. 2025 Jul 1;16(1):5514. doi: 10.1038/s41467-025-61272-5.
Targeted protein degradation (TPD) has rapidly emerged as a powerful modality for drugging previously "undruggable" proteins. TPD employs small molecules like PROTACs and molecular glue degraders (MGD) to induce target protein degradation via the formation of a ternary complex with an E3 ligase. However, the rational design of these degraders is severely hindered by the difficulty of obtaining these ternary structures. Here we introduce DeepTernary, a novel end-to-end deep learning approach using an SE(3)-equivariant encoder and a query-based decoder to accurately and rapidly predict these critical structures. Trained on carefully curated TernaryDB, DeepTernary achieves state-of-the-art performance on PROTAC benchmarks without prior exposure to known PROTACs and shows notable prediction capability on the more challenging MGD benchmark with a blind docking protocol. Remarkably, the buried surface areas calculated from predicted structures correlate with experimental degradation potency metrics. Overall, DeepTernary offers a powerful tool for the development of targeted protein degraders.
靶向蛋白质降解(TPD)已迅速成为一种强大的方法,用于使以前“不可成药”的蛋白质成为可药物作用的靶点。TPD利用小分子如PROTAC和分子胶降解剂(MGD),通过与E3连接酶形成三元复合物来诱导靶蛋白降解。然而,这些降解剂的合理设计因难以获得这些三元结构而受到严重阻碍。在此,我们介绍DeepTernary,一种新颖的端到端深度学习方法,它使用SE(3)等变编码器和基于查询的解码器来准确快速地预测这些关键结构。在精心策划的TernaryDB上进行训练后,DeepTernary在PROTAC基准测试中取得了领先性能,且无需事先接触已知的PROTAC,并且在更具挑战性的MGD基准测试中,通过盲对接协议显示出显著的预测能力。值得注意的是,从预测结构计算出的埋藏表面积与实验降解效力指标相关。总体而言,DeepTernary为靶向蛋白质降解剂的开发提供了一个强大的工具。