LinkerNet: Fragment Poses and Linker Co-Design with 3D Equivariant Diffusion

Part of Advances in Neural Information Processing Systems 36 (NeurIPS 2023) Main Conference Track

Bibtex Paper


Jiaqi Guan, Xingang Peng, PeiQi Jiang, Yunan Luo, Jian Peng, Jianzhu Ma


Targeted protein degradation techniques, such as PROteolysis TArgeting Chimeras (PROTACs), have emerged as powerful tools for selectively removing disease-causing proteins. One challenging problem in this field is designing a linker to connect different molecular fragments to form a stable drug-candidate molecule. Existing models for linker design assume that the relative positions of the fragments are known, which may not be the case in real scenarios. In this work, we address a more general problem where the poses of the fragments are unknown in 3D space. We develop a 3D equivariant diffusion model that jointly learns the generative process of both fragment poses and the 3D structure of the linker. By viewing fragments as rigid bodies, we design a fragment pose prediction module inspired by the Newton-Euler equations in rigid body mechanics. Empirical studies on ZINC and PROTAC-DB datasets demonstrate that our model can generate chemically valid, synthetically-accessible, and low-energy molecules under both unconstrained and constrained generation settings.