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.
Highlights
Purinergic receptor is a potential drug target for neuropathic pain, Alzheimer disease, and prostate cancer
The P2Y1 protein model shares a canonical seven transmembrane helices each flanked by the topological domain like other known G-protein coupled receptors (GPCRs) structures[27,28]
Over 900 compounds were designed using Java Molecular Editor (JME) and translated to structure data file which is compiled in the repository (Table S2 of SI) (Fig. 1A)
Summary
Purinergic receptor is a potential drug target for neuropathic pain, Alzheimer disease, and prostate cancer. The selected P2Y1R-targeted agonist, MRS 2365 increases lactate dehydrogenase and intracellular calcium (Ca2+) levels, in turn induces apoptosis and inhibits the PC-3 cells proliferation[8]. PC-3 and DU-145 PCa cells[19,20], were used to investigate the effect of P2Y1R and novel agonists in cell death and proliferation Many scaffolds such as 1,4-substituted triazoles, pyrimidines or pyrazoles are known for their antitumor activities[21,22,23]. Based on the probability of targeted P2Y1R signaling activation to inhibit PCa cell growth, a library of over 900 structures was built with single variation in the substituents from the different components along with their combinations. Our findings suggested that the identified ligands might potentially help in the treatment of the prostate cancer
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