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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 P2Y 1  receptor (P2Y 1 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  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 P2Y 1 R protein with the ligands. The best hits synthesized were experimentally optimized as a potent P2Y 1  agonists. These ligands exhibits anti-proliferative effect against the PC-3 and DU-145 cells (IC 50  = 15 µM – 33 µM) with significant increase in the calcium level in dose- and time-dependent manner. Moreover, the activation of P2Y 1 R induced the apoptosis via Capase3/7 and ROS signaling pathway. Thus it is evidenced that the newly synthesized ligands, as a P2Y 1 R agonists could potentially act as a therapeutic drug for treating prostate cancer.

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