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These are read out as simplified molecular-input line-entry system (SMILES) format with &gt;98% accuracy, enabling a complete characterization of the molecules in two dimensions. Our model generates three-dimensional representations of the electron density and electrostatic potentials of host\u2013guest systems using a variational autoencoder, and then utilizes these representations to optimize the generation of guests via gradient descent. Finally the guests are converted to SMILES using a transformer. The successful practical application of our model to established molecular host systems, cucurbit[<jats:italic>n<\/jats:italic>]uril and metal\u2013organic cages, resulted in the discovery of 9 previously validated guests for CB[6] and 7 unreported guests (with association constant <jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> ranging from 13.5\u2009M<jats:sup>\u22121<\/jats:sup> to 5,470\u2009M<jats:sup>\u22121<\/jats:sup>) and the discovery of 4 unreported guests for [Pd<jats:sub>2<\/jats:sub>1<jats:sub>4<\/jats:sub>]<jats:sup>4+<\/jats:sup> (with <jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> ranging from 44\u2009M<jats:sup>\u22121<\/jats:sup> to 529\u2009M<jats:sup>\u22121<\/jats:sup>).<\/jats:p>","DOI":"10.1038\/s43588-024-00602-x","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T11:01:51Z","timestamp":1709895711000},"page":"200-209","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Electron density-based GPT for optimization and suggestion of host\u2013guest binders"],"prefix":"10.1038","volume":"4","author":[{"given":"Juan M.","family":"Parrilla-Guti\u00e9rrez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5058-7669","authenticated-orcid":false,"given":"Jaros\u0142aw M.","family":"Granda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Ayme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142 D.","family":"Bajczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Wilbraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-5757","authenticated-orcid":false,"given":"Leroy","family":"Cronin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"602_CR1","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1007\/s10822-013-9672-4","volume":"27","author":"PG Polishchuk","year":"2013","unstructured":"Polishchuk, P. 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