Investigation of D(1) Receptor–Agonist Interactions and D(1)/D(2) Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D(1) receptor agonism and D(1)/D(2) agonist selectivity. A 3D structure model of the D(1) receptor in its agonist-bound state was constructed with a full D(1) agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D(1) agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D(1) and D(2) receptors revealed differences in shape and ligand-interacting features that determine selectivity of D(1) and D(2) receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D(1)/D(2) receptor agonist selectivity were also identified; those were Ser/Cys(3.36), Tyr/Phe(5.38), Ser/Tyr(5.41), and Asn/His(6.55) in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D(1) and D(2) agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.