Synthesis and preclinical validation of novel P2Y1 receptor ligands as a potent anti-prostate cancer agent

Hien Thi Thu Le, Tatu Rimpilainen, Saravanan Konda Mani, Akshaya Murugesan, Olli Yli-Harja, Nuno R Candeias, Meenakshisundaram Kandhavelu

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)


Purinergic receptor is a potential drug target for neuropathic pain, Alzheimer disease, and prostate cancer. Focusing on the structure-based ligand discovery, docking analysis on the crystal structure of P2Y1 receptor (P2Y1R) 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 1) and 636 (compound 2) having highest binding affinity with the docking score of -7.38 and -6.92. We have reported the interaction efficacy and the dynamics of P2Y1R protein with the ligands. The best hits synthesized were experimentally optimized as a potent P2Y1 agonists. These ligands exhibits anti-proliferative effect against the PC-3 and DU-145 cells (IC50 = 15 µM - 33 µM) with significant increase in the calcium level in dose- and time-dependent manner. Moreover, the activation of P2Y1R induced the apoptosis via Capase3/7 and ROS signaling pathway. Thus it is evidenced that the newly synthesized ligands, as a P2Y1R agonists could potentially act as a therapeutic drug for treating prostate cancer.

Original languageEnglish
Article number18938
JournalScientific Reports
Publication statusPublished - 12 Dec 2019
Publication typeA1 Journal article-refereed

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