Homology Model Versus X-ray Structure in Receptor-based Drug Design: A Retrospective Analysis with the Dopamine D3 Receptor

Abstract

Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly true for G protein-coupled receptors (GPCRs), one of the most important targets for approved medicines and current drug discovery projects. However, very few studies have tested their validity in comparison with corresponding crystal structures, especially in a lead optimization perspective. The recent solving of dopamine D3 receptor crystal structure allowed us to assess our historical homology model. We performed a statistical analysis, by docking our in-house lead optimization library of 1500 molecules. We demonstrate here that the refined homology model suits at least as well as the X-ray structure. It is concluded that when the crystal structure of a given GPCR is not available, homology modeling can be an excellent surrogate to support drug discovery efforts.

Keywords: Dopamine D3 receptor; G protein-coupled receptors; docking; homology model; lead optimization.

Figure 1

D3R chemical library from Bioprojet. Ligands are represented through 45 fingerprints and physical properties on a principal component space (principal components PC1, PC2, and PC3). On the left, ligands are colored according to their D3R affinity. It can be seen that each of the four chemical clusters contains all of the affinity range (not all potent ligands belong to the same chemical space). On the right, the library is compared to the Merck Index compounds (red spheres), taken as an archetype of chemical diversity.

Figure 2

Side chains contact plot for X-ray structure of D3R (A) and bovine rhodopsin-based HM (B). (C) Superimposition of α-carbon trace of HM (red) and X-ray structure (blue) of the receptor.

Figure 3

Detail of the supposed binding mode of BP897 in HM (carbon atoms in green) and X-ray structure (carbon atoms in gray). Important residues are labeled in the stereoview. A rmsd of 2.2 Å was calculated between BP897 in HM and in X-ray structure. From both complexes, BP897 has been predicted as an active compound (K_i < 3.5 nM).