Molecular modeling and dynamics studies of the synthetic small molecule agonists with GPR17 and P2Y1 receptor

Abstract

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

Keywords:

• Membrane receptor
• molecular signaling
• GPR17
• P2Y1 receptor
• molecular dynamics
• cAMP

Acknowledgements

We would like to thank Faculty of Medicine and Health Technology, Tampere, Finland for providing instrumental facility for experimental work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval and consent to participate

Not applicable.

Author contributions

K.M.S involved in docking studies and A.M, P.N in biological studies. R.T contributed data analysis of all experiments. A.M and R.T performed quality check and edited the manuscript. A.M, P.N and K.M.S, R.T, and A.M involved in interpretation of the scientific data. M.K and O.Y.H conceived and managed all studies. M.K and K.M.S developed the project. All the authors contributed for the manuscript writing.

Additional information

Funding

P. N acknowledges the Tampere University for the salary support during the project.