Structure-guided molecular design with contrastive 3D protein-ligand learning
For structure-based drug discovery, this work addresses the dual challenge of capturing 3D protein-ligand interactions and navigating ultra-large chemical spaces to identify synthetically accessible candidates.
The paper presents a unified framework combining contrastive 3D structure encoding with autoregressive molecular generation conditioned on commercial compound spaces, achieving competitive zero-shot virtual screening and generating target-specific molecules with favorable predicted binding properties across diverse targets.
Structure-based drug discovery faces the dual challenge of accurately capturing 3D protein-ligand interactions while navigating ultra-large chemical spaces to identify synthetically accessible candidates. In this work, we present a unified framework that addresses these challenges by combining contrastive 3D structure encoding with autoregressive molecular generation conditioned on commercial compound spaces. First, we introduce an SE(3)-equivariant transformer that encodes ligand and pocket structures into a shared embedding space via contrastive learning, achieving competitive results in zero-shot virtual screening. Second, we integrate these embeddings into a multimodal Chemical Language Model (MCLM). The model generates target-specific molecules conditioned on either pocket or ligand structures, with a learned dataset token that steers the output toward targeted chemical spaces, yielding candidates with favorable predicted binding properties across diverse targets.