Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes.
Article Details
- CitationCopy to clipboard
Boeckler F, Lanig H, Gmeiner P
Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes.
J Med Chem. 2005 Feb 10;48(3):694-709.
- PubMed ID
- 15689154 [ View in PubMed]
- Abstract
Focusing on the similarity and divergence of GPCR subtypes and their ligand interactions, we generated dopamine D2, D3, and D4 receptor models based on the rhodopsin crystal structure and refined these with an extensive MM/MD protocol. After validation by diagnostic experimental data, subtype-specific relative positions of TM1, 2, 6, and 7 and bending angles of TM7 were found. To sample the conformational space of the complex, we performed simulated-annealing runs of the receptor protein with the sub-nanomolar antagonist spiperone. Docking a representative set of ligands, we were able to identify one superior model for each subtype when excellent correlations between predicted energies of binding and experimental affinities (r2 = 0.72 for D2, 0.91 for D3 and 0.77 for D4) could be observed. Further analysis revealed general ligand interactions with ASP3.32 and aromatic residues in TM6/7 and individual key interactions with TM1 and TM2 residues of the D3 and D4 receptor models, respectively.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Haloperidol Dopamine D2 receptor Ki (nM) 1.3 N/A N/A Details Haloperidol Dopamine D3 receptor Ki (nM) 10 N/A N/A Details Sulpiride Dopamine D2 receptor Ki (nM) 120 N/A N/A Details Sulpiride Dopamine D3 receptor Ki (nM) 120 N/A N/A Details