{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T23:37:38Z","timestamp":1782257858714,"version":"3.54.5"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2018,5,29]],"date-time":"2018-05-29T00:00:00Z","timestamp":1527552000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Spanish Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["SAF2015-74627-JIN"],"award-info":[{"award-number":["SAF2015-74627-JIN"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003329","name":"Spanish Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["SAF2016-77830-R"],"award-info":[{"award-number":["SAF2016-77830-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Bivalent ligands are increasingly important such as for targeting G protein-coupled receptor (GPCR) dimers or proteolysis targeting chimeras (PROTACs). They contain two pharmacophoric units that simultaneously bind in their corresponding binding sites, connected with a spacer chain. Here, we report a molecular modelling tool that links the pharmacophore units via the shortest pathway along the receptors van der Waals surface and then scores the solutions providing prioritization for the design of new bivalent ligands.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Bivalent ligands of known dimers of GPCRs, PROTACs and a model bivalent antibody\/antigen system were analysed. The tool could rapidly assess the preferred linker length for the different systems and recapitulated the best reported results. In the case of GPCR dimers the results suggest that in some cases these ligands might bind to a secondary binding site at the extracellular entrance (vestibule or allosteric site) instead of the orthosteric binding site.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Freely accessible from the Molecular Operating Environment svl exchange server (https:\/\/svl.chemcomp.com\/).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty422","type":"journal-article","created":{"date-parts":[[2018,5,23]],"date-time":"2018-05-23T11:09:17Z","timestamp":1527073757000},"page":"3857-3863","source":"Crossref","is-referenced-by-count":31,"title":["The size matters? A computational tool to design bivalent ligands"],"prefix":"10.1093","volume":"34","author":[{"given":"Laura","family":"P\u00e9rez-Benito","sequence":"first","affiliation":[{"name":"Laboratori de Medicina Computacional, Unitat de Bioestad\u00edstica, Facultat de Medicina, Universitat Aut\u00f2noma de Barcelona, Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Henry","sequence":"additional","affiliation":[{"name":"Chemical Computing Group, St John\u2019s Innovation Centre Cowley Road, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minos-Timotheos","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University Campus, University of Patras, School of Health Sciences, Rion, Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lopez","sequence":"additional","affiliation":[{"name":"Laboratori de Medicina Computacional, Unitat de Bioestad\u00edstica, Facultat de Medicina, Universitat Aut\u00f2noma de Barcelona, Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pulido","sequence":"additional","affiliation":[{"name":"Combinatorial Chemistry Unit, Barcelona Science Park, Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Bioingenier\u00eda Biomateriales y Nanomedicina (CIBER-BBN), Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Royo","sequence":"additional","affiliation":[{"name":"Combinatorial Chemistry Unit, Barcelona Science Park, Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Bioingenier\u00eda Biomateriales y Nanomedicina (CIBER-BBN), Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnau","family":"Cordom\u00ed","sequence":"additional","affiliation":[{"name":"Laboratori de Medicina Computacional, Unitat de Bioestad\u00edstica, Facultat de Medicina, Universitat Aut\u00f2noma de Barcelona, Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Tresadern","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Pardo","sequence":"additional","affiliation":[{"name":"Laboratori de Medicina Computacional, Unitat de Bioestad\u00edstica, Facultat de Medicina, Universitat Aut\u00f2noma de Barcelona, Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,5,29]]},"reference":[{"key":"2023012712340426300_bty422-B1","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1002\/cmdc.201300286","article-title":"Effect of linker length and composition on heterobivalent ligand-mediated receptor cross-talk between the A1 adenosine and beta2 adrenergic receptors","volume":"8","author":"Barlow","year":"2013","journal-title":"ChemMedChem"},{"key":"2023012712340426300_bty422-B2","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature08650","article-title":"Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor","volume":"463","author":"Bokoch","year":"2010","journal-title":"Nature"},{"key":"2023012712340426300_bty422-B3","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1021\/acs.jmedchem.7b01406","article-title":"Demonstrating in-cell target engagement using a pirin protein degradation probe (CCT367766)","volume":"61","author":"Chessum","year":"2018","journal-title":"J. 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