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Interestingly, two key modulators that elevate cAMP, the A<jats:sub>2A<\/jats:sub> receptor (A<jats:sub>2A<\/jats:sub>R) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A<jats:sub>2A<\/jats:sub>R whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val<jats:sub>84<\/jats:sub> displacement as a novel conformational descriptor of A<jats:sub>2A<\/jats:sub>R activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A<jats:sub>2A<\/jats:sub>R. Subsequent in-vitro analysis confirmed that these compounds bind to the A<jats:sub>2A<\/jats:sub>R and exhibit dual-activity at both the A<jats:sub>2A<\/jats:sub>R and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A<jats:sub>2A<\/jats:sub>R. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.<\/jats:p>","DOI":"10.1186\/s13321-021-00492-5","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T10:05:21Z","timestamp":1614765921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Structure\u2010based identification of dual ligands at the A2AR and PDE10A with anti\u2010proliferative effects in lung cancer cell\u2010lines"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1751-6658","authenticated-orcid":false,"given":"Leen","family":"Kalash","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Winfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-3892","authenticated-orcid":false,"given":"Dewi","family":"Safitri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7421-3282","authenticated-orcid":false,"given":"Marcel","family":"Bermudez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1759-2914","authenticated-orcid":false,"given":"Robert","family":"Glen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-9612","authenticated-orcid":false,"given":"Graham","family":"Ladds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Bender","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"492_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.biocel.2014.04.018","volume":"56","author":"M Hellstrom","year":"2014","unstructured":"Hellstrom M, Harvey AR (2014) Cyclic AMP and the regeneration of retinal ganglion cell axons. 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