Molecular modeling of the human P2Y14 receptor: A template for structure-based design of selective agonist ligands

The P2Y(14) receptor (P2Y(14)R) is a Gi protein-coupled receptor that is activated by uracil nucleotides UDP and UDP-glucose. The P2Y(14)R structure has yet to be solved through X-ray crystallography, but the recent agonist-bound crystal structure of the P2Y(12)R provides a potentially suitable template for its homology modeling for rational structure-based design of selective and high-affinity ligands. In this study, we applied ligand docking and molecular dynamics refinement to a P2Y(14)R homology model to qualitatively explain structure-activity relationships of previously published synthetic nucleotide analogues and to probe the quality of P2Y14R homology modeling as a template for structure-based design. The P2Y(14)R model supports the hypothesis of a conserved binding mode of nucleotides in the three P2Y(12)-like receptors involving functionally conserved residues. We predict phosphate group interactions with R253(6.55), K277(7.35), Y256(6.5)8 and Q260(6.62), nucleobase (anti-conformation) pi-pi stacking with Y102(3.33) and the role of F191(5.42) as a means for selectivity among P2Y(12)-like receptors. The glucose moiety of UDP-glucose docked in a secondary subpocket at the P2Y(14)R homology model. Thus, P2Y(14)R homology modeling may allow detailed prediction of interactions to facilitate the design of high affinity, selective agonists as pharmacological tools to study the P2Y(14)R. Published by Elsevier Ltd.