Minyeong Hwang, Yoorim Gang, Ziseok Lee +5q-bio.QM cs.LG
Lead optimization in structure-based drug design aims to improve target binding while avoiding unintended interactions with off-target pockets. However, existing affinity-driven methods do not explicitly control specificity, whereas current specificity-aware approaches commonly require prior knowledge of off-target structures. We address off-target-agnostic specificity-aware lead optimization by analyzing the geometric mismatch between a ligand and the target pocket. We provide a conservative specificity lower bound for geometrically separated off-targets without requiring access to off-target structures. By metricizing pocket--ligand mismatch, the triangle inequality shows that reducing target--ligand mismatch improves a conservative lower bound on mismatch to a separated off-target class, which can be translated into a specificity lower bound through an empirical geometry--affinity calibration. Motivated by this analysis, we introduce SurfSpec, an off-target-agnostic lead optimization framework that iteratively grows ligands toward under-occupied regions of the target pocket surface. SurfSpec alternates between linker generation toward selected target-surface patches, which provides geometric pseudo-labels, and refinement under a pocket-conditioned ligand prior, which restores these pseudo-labels into valid ligands. On the CrossDocked2020 test set, SurfSpec reduces geometric mismatch and outperforms evaluated off-target-agnostic lead optimization baselines in empirical specificity, while maintaining competitive target-affinity improvement.
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 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 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.