SE(3)-Equivariant Ternary Complex Prediction Towards Target Protein Degradation.

Abstract

Targeted protein degradation (TPD) induced by small molecules has emerged as a rapidly evolving modality in drug discovery, targeting proteins traditionally considered "undruggable." This strategy induces the degradation of target proteins rather than inhibiting their activity, achieving desirable therapeutic outcomes. Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) are the primary small molecules that induce TPD. Both types of molecules form a ternary complex linking an E3 ubiquitin ligase with a target protein, a crucial step for drug discovery. While significant advances have been made in in-silico binary structure prediction for proteins and small molecules, ternary structure prediction remains challenging due to obscure interaction mechanisms and insufficient training data. Traditional methods relying on manually assigned rules perform poorly and are computationally demanding due to extensive random sampling. In this work, we introduce DeepTernary, a novel deep learning-based approach that directly predicts ternary structures in an end-to-end manner using an encoder-decoder architecture. DeepTernary leverages an SE(3)-equivariant graph neural network (GNN) with both intra-graph and ternary inter-graph attention mechanisms to capture intricate ternary interactions from our collected high-quality training dataset, TernaryDB. The proposed query-based Pocket Points Decoder extracts the 3D structure of the final binding ternary complex from learned ternary embeddings, demonstrating state-of-the-art accuracy and speed in existing PROTAC benchmarks without prior knowledge from known PROTACs. It also achieves notable accuracy on the more challenging MGD benchmark under the blind docking protocol. Remarkably, our experiments reveal that the buried surface area calculated from DeepTernary-predicted structures correlates with experimentally obtained degradation potency-related metrics. Consequently, DeepTernary shows potential in effectively assisting and accelerating the development of TPDs for previously undruggable targets.