SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profiles

摘要

We present SynLaD, a latent diffusion framework for small-molecule generation that unifies 3D design objectives (what to make) with synthetic accessibility (how to make it). Current models typically optimize one objective at the expense of the other, creating a bottleneck for discovering high-scoring and experimentally testable molecules. SynLaD combines reaction-constrained generation with pharmacophore-conditioned 3D design by learning a latent space that decodes to both 3D structures and synthesis pathways. An encoder maps molecules to a latent representation used by two decoder heads: (i) a geometric head that reconstructs atom types and coordinates and (ii) an autoregressive synthesis head that outputs synthetic routes in a serialized, reaction-based notation. A diffusion transformer generates novel latents in the learned space, conditioned on pharmacophore profiles. Across analogue-generation tasks for bioactive ligands, SynLaD outperforms existing baselines in synthesizable and diverse hit generation, demonstrating that a single model can produce shape-accurate molecules with feasible synthesis plans.