Demystifying P2Y₁ Receptor Ligand Recognition through Docking and Molecular Dynamics Analyses.

Area of Science:

• Pharmacology
• Biochemistry
• Computational Chemistry

Background:

• The P2Y1 receptor (P2Y1R) is a G protein-coupled receptor involved in various physiological processes.
• Understanding P2Y1R ligand interactions is crucial for developing targeted therapeutics.

Purpose of the Study:

• To analyze the binding modes and structure-activity relationships (SAR) of nucleotide-like bisphosphates and arylurea derivatives at the hP2Y1R.
• To investigate the dynamic interactions of P2Y1R with agonists and antagonists using molecular dynamics (MD) simulations.

Main Methods:

• Molecular docking of 100 nucleotide-like bisphosphates and 46 arylurea derivatives to solved hP2Y1R structures.
• Extensive membrane molecular dynamics (MD) simulations (≥200 ns, triplicate) of receptor complexes with key agonists and antagonists.
• Analysis of ligand-protein interactions, considering nucleotide protonation states and comparing with site-directed mutagenesis (SDM) data.

Main Results:

• Identified key binding patterns and SAR for P2Y1R ligands.
• MD simulations provided insights into ligand-protein interactions, affinity changes, and relevant charged species for nucleotide ligands.
• Predicted conformational changes in the P2Y1R inactive state upon binding of nucleotide agonists.

Conclusions:

• This study elucidates critical molecular interactions governing P2Y1R ligand binding.
• The findings offer valuable insights for the rational design of novel P2Y1R modulators.
• Understanding receptor dynamics and ligand behavior is essential for P2Y1R-targeted drug discovery.