Investigation of D2 Receptor–Agonist Interactions Using a Combination of Pharmacophore and Receptor Homology Modeling

Marcus Malo,Peder Svensson,Lars Brive,Kristina Luthman

doi:10.1002/cmdc.201100545

Abstract

A combined modeling approach was used to identify structural factors that underlie the structure–activity relationships (SARs) of full dopamine D2 receptor agonists and structurally similar inactive compounds. A 3D structural model of the dopamine D2 receptor was constructed, with the agonist (−)-(R)-2-OH-NPA present in the binding site during the modeling procedure. The 3D model was evaluated and compared with our previously published D2 agonist pharmacophore model. The comparison revealed an inconsistency between the projected hydrogen bonding feature (Ser-TM5) in the pharmacophore model and the TM5 region in the structure model. A new refined pharmacophore model was developed, guided by the shape of the binding site in the receptor model and with less emphasis on TM5 interactions. The combination of receptor and pharmacophore modeling also identified the importance of His3936.55 for agonist binding. This convergent 3D pharmacophore and protein structure modeling strategy is considered to be general and can be highly useful in less well-characterized systems to explore ligand–receptor interactions. The strategy has the potential to identify weaknesses in the individual models and thereby provides an opportunity to improve the discriminating predictivity of both pharmacophore searches and structure-based virtual screens.

Highlights

The monoaminergic receptors, including the dopamine (DA) receptors, belong to class A or the rhodopsin-like G-proteincoupled receptor (GPCR) superfamily
All full agonists except (R)-3-PPP and A70108 (11/13 OPLS generated set of ligands), and all but one ((S)-3-PPP) of the partial agonists (4/5) fit into the pharmacophore model
For further evaluation we screened the pharmacophore model against a set of MMFF(s)-generated conformations, which resulted in the loss of one additional active ligand ((R,R)-PHNO) (10/13)

Summary

Introduction

The monoaminergic receptors, including the dopamine (DA) receptors, belong to class A or the rhodopsin-like G-proteincoupled receptor (GPCR) superfamily. TM6 contains a cluster of hydrophobic amino acids that are involved in agonist binding and in the activation of the GPCRs. In particular, Phe3906.52 is important for direct binding of the catechol or corresponding aromatic rings in agonists,[34,50] while Phe3896.51 has been suggested to interact with the positively charged basic nitrogen atom of the ligands.[50] In binding studies, Lundstrçm et al.[51] have shown that a mutation of a histidine residue located in TM6 in the D3 receptor (His3496.55!Leu) affects binding of dopamine, but not binding of 7-OH-DPAT. The latter study included quinpirole binding data, and showed that the affinity of quinpirole for D2high

Receptor–Agonist Interactions

Results and Discussion

Results of the pharmacophore model search

Conclusions