Sesame: Structure-Aware Molecular Generation via Spatial Density-Map Conditioning

Researchers introduced Sesame, a diffusion-based molecular generation model that conditions on partial molecular structure and protein pockets via spatial density maps, enabling both de novo drug design and fragment-based lead optimization. The model uses a novel spatial pairformer module and joint denoising of atom types, bonds, and positions, with trajectory finetuning to improve generation quality.

arXiv:2606.23856v1 Announce Type: new Abstract: Generative molecular models for drug design are a promising direction with much active research. In the next phase of computational drug design, such models will need to understand small molecule structure and protein-ligand interactions, and they will need to possess the machinery to generate molecules \textit{de novo}. Incorporating each feature poses a critical challenge. Equally important, yet often treated as secondary, is the ability to grow a molecule from a partial starting point -- a scaffold or fragment supplied by a chemist -- which is the central operation of lead optimization. We present Sesame Spatial Evoformer for a Structure-Aware Molecular Engine , a diffusion-based molecular generation model that leverages a novel spatial pairformer module to condition on partial molecular structure and the surrounding protein pocket, both expressed as continuous spatial density maps. This single conditioning mechanism supports both \textit{de novo} generation and fragment-conditioned lead optimization, letting a medicinal chemist prune a hit to a scaffold and have Sesame grow it in productive ways. In addition to this module, we also introduce a diffusion framework for joint denoising of atom types, bond types, and positions, along with a trajectory finetuning scheme that trains on the model's own sampling rollouts to improve generation quality. Sesame is trained on a large corpus of ligand-only and protein-ligand datasets.