The human Guanine Protein coupled membrane Receptor 17 (hGPR17), an orphan receptor that activates uracil nucleotides and cysteinyl leukotrienes is considered as a crucial target for the neurodegenerative diseases. Yet, the detailed molecular interaction of potential synthetic ligands of GPR17 needs to be characterized. Here, we have studied a comparative analysis on the interaction specificity of GPR17-ligands with hGPR17 and human purinergic G protein-coupled receptor (hP2Y1) receptors. Previously, we have simulated the interaction stability of synthetic ligands such as T0510.3657, AC1MLNKK, and MDL29951 with hGPR17 and hP2Y1 receptor in the lipid environment. In the present work, we have comparatively studied the protein-ligand interaction of hGPR17-T0510.3657 and P2Y1-MRS2500. Sequence analysis and structural superimposition of hGPR17 and hP2Y1 receptor revealed the similarities in the structural arrangement with the local backbone root mean square deviation (RMSD) value of 1.16 Å and global backbone RMSD value of 5.30 Å. The comparative receptor-ligand interaction analysis between hGPR17 and hP2Y1 receptor exposed the distinct binding sites in terms of geometrical properties. Further, the molecular docking of T0510.3657 with the hP2Y1 receptor have shown non-specific interaction. The experimental validation also revealed that Gi-coupled activation of GPR17 by specific ligands leads to the adenylyl cyclase inhibition, while there is no inhibition upon hP2Y1 activation. Overall, the above findings suggest that T0510.3657-GPR17 binding specificity could be further explored for the treatment of numerous neuronal diseases. Communicated by Ramaswamy H. Sarma.

12 Aug 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Preclinical Validation of Novel Indole Derivatives as a GPR17 Agonist for Glioblastoma Treatment

Q1 · MEDICINE

Article

Author: Konda Mani, Saravanan ; Candeias, Nuno R. ; Doan, Phuong ; Murugesan, Akshaya ; Rimpilainen, Tatu ; Nguyen, Phung ; Kandhavelu, Meenakshisundaram ; Yli-Harja, Olli

The discovery of a potential ligand-targeting G protein-coupled receptor 17 (GPR17) is important for developing chemotherapeutic agents against glioblastoma multiforme (GBM). We used the integration of ligand- and structure-based cheminformatics and experimental approaches for identifying the potential GPR17 ligand for GBM treatment. Here, we identified a novel indoline-derived phenolic Mannich base as an activator of GPR17 using molecular docking of over 6000 indoline derivatives. One of the top 10 hit molecules, CHBC, with a glide score of -8.390 was synthesized through a multicomponent Petasis borono-Mannich reaction. The CHBC-GPR17 interaction leads to a rapid decrease of cAMP and Ca²⁺. CHBC exhibits the cytotoxicity effect on GBM cells in a dose-dependent manner with an IC₅₀ of 85 μM, whereas the known agonist MDL29,951 showed a negligible effect. Our findings suggest that the phenolic Mannich base could be a better GPR17 agonist than MDL29,951, and further uncovering their pharmacological properties could potentiate an inventive GBM treatment.

01 Jan 2018·International Journal of Biological MacromoleculesQ1 · CHEMISTRY

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

Q1 · CHEMISTRY

Article

Author: Palanivel, Suresh ; Saravanan, Konda Mani ; Kandhavelu, Meenakshisundaram ; Yli-Harja, Olli

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 inhibit 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	OM	University of Sultan Qaboos	05 Sep 2018

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