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Generative SBDD methods leverage structural data of drugs with their protein targets to propose new drug candidates. However, most existing methods focus exclusively on bottom-up de novo design of compounds or tackle other drug development challenges with task-specific models. The latter requires curation of suitable datasets, careful engineering of the models and retraining from scratch for each task. Here we show how a single pretrained diffusion model can be applied to a broader range of problems, such as off-the-shelf property optimization, explicit negative design and partial molecular design with inpainting. We formulate SBDD as a three-dimensional conditional generation problem and present DiffSBDD, an SE(3)-equivariant diffusion model that generates novel ligands conditioned on protein pockets. Furthermore, we show how additional constraints can be used to improve the generated drug candidates according to a variety of computational metrics.<\/jats:p>","DOI":"10.1038\/s43588-024-00737-x","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T10:03:23Z","timestamp":1733738603000},"page":"899-909","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":178,"title":["Structure-based drug design with equivariant diffusion models"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9924-6921","authenticated-orcid":false,"given":"Arne","family":"Schneuing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2988-0374","authenticated-orcid":false,"given":"Yuanqi","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-3320","authenticated-orcid":false,"given":"Kieran","family":"Didi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arian","family":"Jamasb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilia","family":"Igashov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weitao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4441-7225","authenticated-orcid":false,"given":"Carla","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2708-8992","authenticated-orcid":false,"given":"Tom L.","family":"Blundell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0540-5053","authenticated-orcid":false,"given":"Pietro","family":"Lio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Welling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bronstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7377-8636","authenticated-orcid":false,"given":"Bruno","family":"Correia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"737_CR1","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.chembiol.2003.09.002","volume":"10","author":"AC Anderson","year":"2003","unstructured":"Anderson, A. 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