Ligand discovery from a dopamine D3 receptor homology model and crystal structure


G protein–coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery increased. Unfortunately, for most GPCRs no experimental structures are available. The determination of the D3 receptor structure and the challenge to the community to predict it enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities ranging from 0.2 to 3.1 μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities ranging from 0.3 to 3.0 μM. One of the new ligands from the homology model screen was optimized for affinity to 81 nM. The feasibility of docking screens against modeled GPCRs more generally is considered.

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Figure 1: Predicted structure of the dopamine D3 receptor binding site.
Figure 2: Predicted binding modes of ligands found from the homology model screen.
Figure 3: Dose-response curves of discovered ligands.
Figure 4: Predicted binding modes of ligands found from the crystal structure screen.


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We thank Q. Yang and K. Sharp for help with 3K-ENM, M. Burlingame with help with compound LC/MS and G. Barnea (Brown University) for supplying beginning Tango constructs and a plasmid encoding the human V2 Tango receptor. We thank OpenEye Scientific Software for the use of OEChem and Omega. Supported by US National Institutes of Health grants GM59957 and GM71630 (to B.K.S.), U54GM093342 (to A. Sali and B.K.S.), GM71790 and R01GM54762 (to A. Sali), the National Institutes of Mental Health Psychoactive Drug Screening Program (to B.L.R.), postdoctoral fellowships from the Knut and Alice Wallenberg Foundation (to J.C.) and National Research Service Award-Kirschstein fellowships F32GM096544 (to R.G.C.) and F32GM088991 (to A. Schlessinger).

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Docking and homology modeling was conducted by J.C. and R.G.C., the latter with assistance from H.F., A. Schlessinger and A. Sali, J.J.I. and B.K.S. assisted with compound selection and strategy, J.J.I. lent expertise with the DOCK Blaster toolchain and fixed problems with ZINC. B.L.R. and V.S. were responsible for the pharmacological guidance as to the appropriate specificity tests, while V.S. conducted all the experiments. All authors contributed to the writing of the manuscript.

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Correspondence to Bryan L Roth or Brian K Shoichet.

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Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 1772 kb)

Supplementary Data Set 1

SupplementaryDataset1.xlsx (XLSX 146 kb)

Supplementary Data Set 2

model_receptor.txt (TXT 137 kb)

Supplementary Data Set 3

model_ligands.txt (TXT 20 kb)

Supplementary Data Set 4

crystal_receptor.txt (TXT 138 kb)

Supplementary Data Set 5

crystal_ligands.txt (TXT 16 kb)

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Carlsson, J., Coleman, R., Setola, V. et al. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol 7, 769–778 (2011).

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