TriGlue：一個受生物學啟發的生成模型，用於生成分子膠誘導的三元複合物

摘要

分子膠降解劑已成為一種有前景的標靶蛋白質降解策略，其原理是誘導E3泛素連接酶與標靶蛋白之間形成三元複合物。儘管具有治療潛力，分子膠的計算設計仍 largely 未被充分探索。與傳統的基於結構的藥物設計不同，分子膠設計受制於未知的蛋白質-蛋白質介面，且需要同時模擬配體生成、蛋白質-蛋白質對接以及三元複合物組裝。在本工作中，我們將分子膠設計表述為一個三元複合物生成問題，並提出一個受生物啟發的生成框架 TriGlue。受分子膠作用機制啟發，我們將三元複合物生成分解為兩個耦合階段：介面估計與介面條件下的複合物生成。首先，我們開發了一個 SE(3)-等變介面估計模組，可從未結合的單體結構預測受幾何約束的蛋白質-蛋白質介面。其次，我們引入一個介面條件下的三元流匹配網路，該網路聯合生成分子膠並預測組裝三元複合物所需的剛體變換。大量實驗表明，TriGlue 能生成化學上有效的分子並產生合理的三元複合物，這凸顯了受生物啟發的生成建模在加速分子膠發現方面的潛力。我們的代碼可在 https://github.com/yuliangyan0807/molecular-glue-design 取得。

English

Molecular glue degraders have emerged as a promising strategy for targeted protein degradation by inducing ternary complex formation between an E3 ubiquitin ligase and a target protein. Despite their therapeutic potential, computational design of molecular glues remains largely unexplored. Unlike conventional structure-based drug design, molecular glue design is governed by the unknown protein-protein interface and requires the simultaneous modeling of ligand generation, protein-protein docking, and ternary complex assembly. In this work, we formulate molecular glue design as a ternary complex generation problem and propose a biology-inspired generative framework, TriGlue. Motivated by the mechanism of molecular glue action, we decompose ternary complex generation into two coupled stages: interface estimation and interface-conditioned complex generation. First, we develop an SE(3)-equivariant interface estimation module that predicts a geometrically constrained protein-protein interface from unbound monomer structures. Second, we introduce an interface-conditioned ternary flow matching network that jointly generates the molecular glue and predicts the rigid-body transformation required to assemble the ternary complex. Extensive experiments demonstrate that TriGlue generates chemically valid molecules and produces plausible ternary complexes, which highlight the potential of biology-inspired generative modeling for accelerating molecular glue discovery. Our code is available at https://github.com/yuliangyan0807/molecular-glue-design.