{"ID":6620480,"CreatedAt":"2026-07-15T01:01:48.440468303Z","UpdatedAt":"2026-07-15T03:28:55.185153975Z","DeletedAt":null,"paper_url":"https://arxiv.org/abs/2607.12349","arxiv_id":"2607.12349","title":"Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization","abstract":"Drug discovery and development is time-consuming and resource-intensive, motivating computational approaches such as diffusion models for de novo drug design. Many such models follow the structure-based drug design (SBDD) paradigm, generating molecules to fit a target binding pocket. However, existing diffusion-based SBDD methods typically couple pocket and ligand representation learning, model interactions only at the atom level, and prioritize binding affinity over other developability properties. Here, we introduce conDitar-dev, a conditional diffusion-based SBDD framework for generating ligands with strong binding affinities and favorable ADMET properties. It consists of three modules: msPRL, a pretrained multi-scale pocket representation learning module; conDitar, a pocket-conditioned diffusion model guided by msPRL representations; and paOPT, a generation-time method for optimizing ligand developability. On a newly curated benchmark of human disease targets, conDitar outperforms state-of-the-art SBDD baselines, achieving an average binding score of -8.85 kcal/mol. Across five ADMET properties, conDitar-dev improves performance by up to 73% over conDitar. To further validate the abilities of conDitar-dev to generate developable molecules, we have applied it to two validated druggable targets: programmed death-ligand 1 (PD-L1) and colony-stimulating factor 1 receptor (CSF1R) proteins. Top-ranked generatively designed molecules and their analogs have been experimentally synthesized and biologically tested. Two molecules generated directly by conDitar-dev for PD-L1 exhibited SPR-derived $K_D$ values of 3.49 and 3.75 $μ$M, respectively. Hit expansion based on conDitar-dev-designed molecules identified selective CSF1R inhibitors with IC$_{50}$ values as low as 200 nM, while also uncovering opportunities for drug repositioning.","short_abstract":"Drug discovery and development is time-consuming and resource-intensive, motivating computational approaches such as diffusion models for de novo drug design. Many such models follow the structure-based drug design (SBDD) paradigm, generating molecules to fit a target binding pocket. However, existing diffusion-based S...","url_abs":"https://arxiv.org/abs/2607.12349","url_pdf":"https://arxiv.org/pdf/2607.12349v1","authors":"[\"Ruoxi Gao\",\"Jiangweizhi Peng\",\"Ziqi Chen\",\"Frazier N. Baker\",\"David C. Kombo\",\"John L. Kane\",\"Andrew A. Scholte\",\"Yi Li\",\"Matthew J. LaMarche\",\"Luigi I. Iconaru\",\"Hans-Peter Biemann\",\"Mingyi Hong\",\"Xia Ning\"]","published":"2026-07-14T04:52:25Z","proceeding":"cs.LG","tasks":"[\"cs.LG\"]","methods":"[\"Diffusion Model\",\"Generative Adversarial Network\"]","has_code":false}