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Focusing on the structure-based ligand discovery, docking analysis on the crystal structure of P2Y<jats:sub>1<\/jats:sub> receptor (P2Y<jats:sub>1<\/jats:sub>R) with 923 derivatives of 1-indolinoalkyl 2-phenolic compound is performed to understand the molecular insights of the receptor. The structural model identified the top novel ligands, 426 (compound <jats:bold>1<\/jats:bold>) and 636 (compound <jats:bold>2<\/jats:bold>) having highest binding affinity with the docking score of \u22127.38 and \u22126.92. We have reported the interaction efficacy and the dynamics of P2Y<jats:sub>1<\/jats:sub>R protein with the ligands. The best hits synthesized were experimentally optimized as a potent P2Y<jats:sub>1<\/jats:sub> agonists. These ligands exhibits anti-proliferative effect against the PC-3 and DU-145 cells (IC<jats:sub>50<\/jats:sub>\u2009=\u200915\u2009\u00b5M \u2013 33\u2009\u00b5M) with significant increase in the calcium level in dose- and time-dependent manner. Moreover, the activation of P2Y<jats:sub>1<\/jats:sub>R induced the apoptosis via Capase3\/7 and ROS signaling pathway. Thus it is evidenced that the newly synthesized ligands, as a P2Y<jats:sub>1<\/jats:sub>R agonists could potentially act as a therapeutic drug for treating prostate cancer.<\/jats:p>","DOI":"10.1038\/s41598-019-55194-8","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T15:11:38Z","timestamp":1576163498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Synthesis and preclinical validation of novel P2Y1 receptor ligands as a potent anti-prostate cancer agent"],"prefix":"10.1038","volume":"9","author":[{"given":"Hien Thi Thu","family":"Le","sequence":"first","affiliation":[]},{"given":"Tatu","family":"Rimpilainen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-234X","authenticated-orcid":false,"given":"Saravanan","family":"Konda Mani","sequence":"additional","affiliation":[]},{"given":"Akshaya","family":"Murugesan","sequence":"additional","affiliation":[]},{"given":"Olli","family":"Yli-Harja","sequence":"additional","affiliation":[]},{"given":"Nuno R.","family":"Candeias","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4986-055X","authenticated-orcid":false,"given":"Meenakshisundaram","family":"Kandhavelu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"55194_CR1","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1111\/bju.13059","volume":"117","author":"M Van Hemelrijck","year":"2016","unstructured":"Van Hemelrijck, M. et al. 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