{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:09:07Z","timestamp":1774440547845,"version":"3.50.1"},"reference-count":89,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key R&D Program of China","award":["2017YFC1104400"],"award-info":[{"award-number":["2017YFC1104400"]}]},{"name":"the Fundamental Research Funds for the Central Universities, Nankai University","award":["63201231"],"award-info":[{"award-number":["63201231"]}]},{"name":"the Fundamental Research Funds for the Central Universities, Nankai University","award":["63201228"],"award-info":[{"award-number":["63201228"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Adenosine receptors (ARs) have been demonstrated to be potential therapeutic targets against Parkinson\u2019s disease (PD). In the present study, we describe a multistage virtual screening approach that identifies dual adenosine A<jats:sub>1<\/jats:sub> and A<jats:sub>2A<\/jats:sub> receptor antagonists using deep learning, pharmacophore models, and molecular docking methods. Nineteen hits from the ChemDiv library containing 1,178,506 compounds were selected and further tested by <jats:italic>in vitro<\/jats:italic> assays (cAMP functional assay and radioligand binding assay); of these hits, two compounds (C8 and C9) with 1,2,4-triazole scaffolds possessing the most potent binding affinity and antagonistic activity for A<jats:sub>1<\/jats:sub>\/A<jats:sub>2A<\/jats:sub> ARs at the nanomolar level (pK<jats:sub>i<\/jats:sub> of 7.16\u20137.49 and pIC<jats:sub>50<\/jats:sub> of 6.31\u20136.78) were identified. Further molecular dynamics (MD) simulations suggested similarly strong binding interactions of the complexes between the A<jats:sub>1<\/jats:sub>\/A<jats:sub>2A<\/jats:sub> ARs and two compounds (C8 and C9). Notably, the 1,2,4-triazole derivatives (compounds C8 and C9) were identified as the most potent dual A<jats:sub>1<\/jats:sub>\/A<jats:sub>2A<\/jats:sub> AR antagonists in our study and could serve as a basis for further development. The effective multistage screening approach developed in this study can be utilized to identify potent ligands for other drug targets.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008821","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T17:23:22Z","timestamp":1616174602000},"page":"e1008821","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Discovery of novel dual adenosine A1\/A2A receptor antagonists using deep learning, pharmacophore modeling and molecular 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