Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D₁-like and D₂-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. Results: Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D₁R-like selective ligands binding. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands.

Background: Communication within a protein complex is mediated by physical interactions made among the protomers. Evidence for both the allosteric regulation present among the protomers of the protein oligomer and of the direct effect of membrane composition on this regulation has made it essential to investigate the underlying molecular mechanism that drives oligomerization, the type of interactions present within the complex, and to determine the identity of the interaction interface. This knowledge allows a holistic understanding of dynamics and also modulation of the function of the resulting oligomers/signalling complexes. G-Protein-Coupled Receptors (GPCRs), which are targeted by 40% of currently prescribed drugs in the market, are widely involved in the formation of such physiological oligomers/signalling complexes. Scope: This review highlights the importance of studying Protein-Protein Interactions (PPI) by using a combination of data obtained from cutting-edge experimental and computational methods that were developed for this purpose. In particular, we focused on interaction interfaces found at GPCR oligomers as well as signalling complexes, since any problem associated with these interactions causes the onset of various crucial diseases. Conclusion: In order to have a holistic mechanistic understanding of allosteric PPIs that drive the formation of GPCR oligomers and also to determine the composition of interaction interfaces with respect to different membrane compositions, it is essential to combine both relevant experimental and computational data. In this way, efficient and specific targeting of these interaction interfaces in oligomers/ complexes can be achieved. Thus, effective therapeutic molecules with fewer side effects can be designed to modulate the function of these physiologically important receptor family.