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Our approach leverages the conditioning of the ligand generation process on reference molecules located within a specific protein pocket. By doing so, PoLiGenX generates shape-similar ligands that are adapted to the target pocket, enabling effective applications in target-aware hit expansion and hit optimization. Our experimental results underscore the efficacy of PoLiGenX in advancing ligand design. Notably, docking analyses reveal that the ligands generated by PoLiGenX show enhanced binding affinities relative to their reference molecules, all while retaining a similar molecular shape, but\u00a0 also retaining better poses with lower strain energies and less steric clashes. Furthermore, the model promotes substantial chemical diversity, facilitating the exploration of broader and more varied chemical spaces. Importantly, the generated ligands were assessed for drug-likeness using Lipinski\u2019s rule of five, demonstrating superior adherence to drug-likeness criteria compared to the reference dataset. This work represents a step forward in the controlled and precise generation of therapeutically relevant <jats:italic>de novo<\/jats:italic> ligands tailored for specific protein targets, contributing to progress in computational drug discovery and ligand design.<\/jats:p>","DOI":"10.1186\/s13321-025-01028-x","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T19:25:36Z","timestamp":1748719536000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Equivariant diffusion for structure-based de novo ligand generation with latent-conditioning"],"prefix":"10.1186","volume":"17","author":[{"given":"Tuan","family":"Le","sequence":"first","affiliation":[]},{"given":"Julian","family":"Cremer","sequence":"additional","affiliation":[]},{"given":"Djork-Arn\u00e9","family":"Clevert","sequence":"additional","affiliation":[]},{"given":"Kristof T.","family":"Sch\u00fctt","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"1028_CR1","doi-asserted-by":"publisher","first-page":"14954","DOI":"10.1039\/D4SC03523B","volume":"15","author":"Julian Cremer","year":"2024","unstructured":"Cremer Julian, Le Tuan, No\u00e9 Frank, Clevert Djork-Arn\u00e9, Sch\u00fctt Kristof T (2024) Pilot: equivariant diffusion for pocket-conditioned de novo ligand generation with multi-objective guidance via importance sampling. 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