Investigation of D1 Receptor–Agonist Interactions and D1/D2 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 D₁ receptor agonism and D₁/D₂ agonist selectivity. A 3D structure model of the D₁ receptor in its agonist-bound state was constructed with a full D₁ 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 D₁ 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 D₁ and D₂ receptors revealed differences in shape and ligand-interacting features that determine selectivity of D₁ and D₂ 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 D₁/D₂ receptor agonist selectivity were also identified; those were Ser/Cys³·³⁶, Tyr/Phe⁵·³⁸, Ser/Tyr⁵·⁴¹, and Asn/His⁶·⁵⁵ 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 D₁ and D₂ 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.