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Identification of novel GPR17-agonists by structural bioinformatics and signaling activation

Research output: Contribution to journalArticleScientificpeer-review


Original languageEnglish
Pages (from-to)901-907
JournalInternational Journal of Biological Macromolecules
Early online date2017
Publication statusPublished - 2018
Publication typeA1 Journal article-refereed


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.

Publication forum classification

Field of science, Statistics Finland