G Protein-coupled Receptor 17 (GPR17) is phylogenetically related to the purinergic receptors emerged as a potential drug target for multiple sclerosis, Parkinson disease, Alzheimer disease and cancer. Unfortunately, the crystal structure of GPR17 is unresolved. With the interest in structure-based ligand discovery, we modeled the structure of GPR17. The model allowed us to identify two novel agonists, AC1MLNKK and T0510.3657 that selectively activate GPR17 which exhibit better interaction properties than previously known ligand, MDL29951. We report detailed protein-ligand interactions and the dynamics of GPR17-ligand interaction by molecular docking and molecular dynamics experiments. Ex vivo validation of GPR17-ligand interaction provides evidence that ligand T0510-3657 and AC1MLNKK inhibits the cAMP levels in GPR17-HEK293T cells, with a pEC50 of 4.79 and 4.64, respectively. In silico and ex vivo validation experiments provided the deep understanding of ligand binding with GPR17 and the present findings reported here may lead to use these two compounds as a potential activator of GPR17 for therapeutic intervention.
In this work, we report the anticancer properties of a series of 11 chemically synthesized alkylaminophenols against human osteosarcoma U2OS tumor cell line. Several assays including cytotoxicity, inhibitor kinetic study, cell migration, Annexin-V/PI double staining, reactive oxygen species (ROS) and caspase 3/7 assays were conducted on this cell line. Cytotoxic 2-((3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol was determined to have an IC50 value of 36.6 µM against U2OS cells and it also inhibits the cell growth in time-dependent manner. The potent activity of lead compound against the growth of multiple cell lines, U2OS, MG-65 and HEK-293T, confirms the osteosarcoma cell specific inhibition. Further studies indicated that such compoundis an inhibitor of metastatic property of tumor cells and inducing apoptosis agent. The ability of increasing ROS and inducing caspases 3 and 7 further confirm the contribution of programmed cell death in U2OS and HEK-293T cells. Additionally, four compounds based on the 2-(indolin-1-yl(aryl)methyl)-4-nitrophenol core were also identified to be cytotoxic with IC50 values in the 66 – 88 µM range. This work further demonstrates the anticancer properties of phenol derivatives, adding one more entry to the collection of promising chemotherapeutic agents for cancer treatment.