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

Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK. (2011) Nat Chem Biol 7, 769-78. PMCID: PMC3197762

As part of the EFI’s early outreach efforts, an integrated modeling and docking strategy was applied by the EFI Computation Core to predict ligands for the dopamine D3 GPCR in a collaboration with the Psychoactive Drug Screening Program (PDSP) center.  This effort extended the utility of modeling expertise and strategies that EFI members initially developed for EFI projects.

As part of the EFI’s early outreach efforts, an integrated modeling and docking strategy was applied by the EFI Computation Core to predict ligands for the dopamine D3 GPCR in a collaboration with the Psychoactive Drug Screening Program (PDSP) center.  This effort extended the utility of modeling expertise and strategies that EFI members initially developed for EFI projects.

As part of the EFI’s early outreach efforts, an integrated modeling and docking strategy was applied by the EFI Computation Core to predict ligands for the dopamine D3 GPCR in a collaboration with the Psychoactive Drug Screening Program (PDSP) center.  This effort extended the utility of modeling expertise and strategies that EFI members initially developed for EFI projects.

As part of the EFI’s early outreach efforts, an integrated modeling and docking strategy was applied by the EFI Computation Core to predict ligands for the dopamine D3 GPCR in a collaboration with the Psychoactive Drug Screening Program (PDSP) center.  This effort extended the utility of modeling expertise and strategies that EFI members initially developed for EFI projects.

As part of the EFI’s early outreach efforts, an integrated modeling and docking strategy was applied by the EFI Computation Core to predict ligands for the dopamine D3 GPCR in a collaboration with the Psychoactive Drug Screening Program (PDSP) center.  This effort extended the utility of modeling expertise and strategies that EFI members initially developed for EFI projects.

Abstract

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 D(3) 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. (a) Comparison of the homology model of the dopamine D3 receptor in complex with eticlopride (light blue) to the crystal structure (yellow), visualized with PyMOL. The structures have been aligned using 15 binding-site residues. Polar interactions for the crystal structure are shown in black dashed lines. (b) Chemical structure of eticlopride (compound 1).

Figure 2: Predicted binding modes of ligands found from the homology model screen. (a–d) Predicted binding poses for four ligands discovered in the docking screen against the dopamine D3 receptor homology model, visualized with University of California San Francisco (UCSF) Chimera: 3 (a), 4 (b), 6 (c) and 7 (d). (e,f) Predicted binding modes for the two analogs of 3 based on docking to the homology model: 56 (e) and 57 (f). TM, transmembrane helices; EL2, extracellular loop 2.

Figure 3: Dose-response curves of discovered ligands. (a–f) Representative radioligand ([3H]N-Methylspiperone) competition binding isotherms for compounds 3 (a), 4 (b), 7 (c), 28 (d), 30 (e) and 31 (f). Data for a reference compound (chlorpromazine, black curve) are shown along with data for the test compound (red curve). Assays are performed using a final radioligand concentration between 0.5 × KD and 1 × KD, where KD equals the radioligand dissociation constant, which is determined for each crude membrane preparation by radioligand saturation binding analysis. Data represent mean values ± s.e.m, performed on triplicate experiments.

Figure 4: Predicted binding modes of ligands found from the crystal structure screen. Predicted binding poses for the ligands discovered in the docking screen against the dopamine D3 receptor crystal structure, visualized with UCSF Chimera: 28 (a), 29 (b), 31 (c) and 32 (d).

Reprinted by permission from Macmillan Publishers Ltd: Nature Chemical Biology, © 2011