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

ABSTRACT: 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.

SUBMITTER: Le HTT 

PROVIDER: S-EPMC6908675 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature