A theoretical study to investigate D2DAR/D4DAR selectivity: receptor modeling and molecular docking of dopaminergic ligands (original) (raw)
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Journal of Medicinal Chemistry, 1994
We present the first model of dopamine D2 receptor transmembrane helices constructed directly from the bacteriorhodopsin (bR) coordinates derived from two-dimensional electron diffraction experiments. We have tested this model by its ability to accommodate rigid agonist and semirigid antagonist molecules which were docked into the putative binding pocket with stabilizing interactions. The model is consistent with structure-activity relationships of agonists and antagonists that interact with the receptor. It also illuminates data on a Na+ site for regulation of receptor function. The plausibility of the model is increased by its consistency with many mutagenesis studies on G protein-coupled receptors. Further, this model provides a basis to suggest testable molecular mechanisms for changes in the D2 conformational states for high-and low-affinity binding and signal transduction. Changes in the conformational state of the receptor are hypothesized to be due partly to movement of helix 7. In contrast to the model presented here, other published models were built using ideal helical structures or following the sense of the bacteriorhodopsin structure rather than the actual available coordinates. The presented model for the dopamine G protein-coupled receptor can be reconciled with the recent rhodopsin projection structure (Schertler, G. F. X.; Villa, C.; Henderson, R. Projection Structure of Rhodopsin. Nature 1993,362, [770][771][772].
PLoS ONE, 2012
Dopamine (DA) receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders. The lack of structural information about GPCRs and their ligand complexes has prompted the development of homology models of these proteins aimed at structure-based drug design. Crystal structure of human dopamine D 3 (hD 3 ) receptor has been recently solved. Based on the hD 3 receptor crystal structure we generated dopamine D 2 and D 3 receptor models and refined them with molecular dynamics (MD) protocol. Refined structures, obtained from the MD simulations in membrane environment, were subsequently used in molecular docking studies in order to investigate potential sites of interaction. The structure of hD 3 and hD 2L receptors was differentiated by means of MD simulations and D 3 selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental K i was obtained for hD 3 and hD 2L receptor ligands.
Modeling of ligand binding to dopamine D2 receptor
Journal of the Serbian Chemical Society, 2014
The dopaminic receptors for a long time have been major targets for the development of new small molecules with high affinity and selectivity to treat psychiatric disorders, neurodegeneration, and drug abuse, and in other therapeutic areas. In the absence of a 3D structure for the human dopamine D2 (HDD2) receptor, the efforts for the discovery and design of new potential drugs rely on comparative models generation, docking and pharmacophore development studies. To obtain a better understanding of the HDD2 receptor binding site and the ligand-receptor interactions, a homology model of the HDD2 receptor based on the X-ray structure of the β2-adrenergic receptor was built and used to dock a set of partial agonists of the HDD2 receptor. The main characteristics of the binding mode for the HDD2 partial agonists set are given by the particular folding of a ligand and a complex network of contacts represented by stacking interactions, salt bridge and hydrogen bond formation. The characterization of the binding mode of the partial agonists at the HDD2 receptor provides the information required to generate pharmacophore models, which represent essential information for future virtual screening studies in order to identify new potential HDD2 partial agonists.
Three amino acids in the D 2 dopamine receptor regulate selective ligand function and affinity
Journal of Neurochemistry, 2009
The D2 dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D4 subtype of dopamine receptor were tested on wild-type and mutant D2 receptors. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D2 receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D4 amino acids. The two ligands with the greatest improvement in affinity for the D2 mutant receptor [i.e., 3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine (L-750,667) and 1-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine (RBI-257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole’s functional response in the mutant did not significantly reduce quinpirole’s functional response in the wild-type D2 receptor. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D2 but an antagonist at both the mutant D2 and wild-type D4 receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D2 dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Consistent with the experimental data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D2, mutant D2, or wild-type D4 receptors.
Research Journal of Pharmaceutical, Biological and Chemical Sciences
An analysis of the relationships between electronic structure and dopamine D 2 receptor binding affinity was carried out for a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines. Local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) level after full geometry optimization. A statistically significant equation relating several local atomic reactivity indices with the binding affinity was obtained. From the results, a partial 2D pharmacophore is built, containing several sites that can be used for substitution enhancing binding affinity. An important conclusion is that because the common skeleton hypothesis is producing once more excellent results, the results reported here must serve as a guide for correct docking procedures.
Selectivity of dopamine D1 and D2 receptor agonists – A combined computational approach
2012
Dopamine (DA) is an endogenous neurotransmitter acting in the central nervous system. DA plays a key role in many vital brain functions such as behavior, cognition, motor activity, learning, and reward. Dopamine receptors belong to the rhodopsin like family of G-protein coupled receptors (GPCRs). There are five subtypes of DA receptors (D1-D5), which are further divided into two main families based on sequence similarities and their coupling to intracellular signaling (D1and D2-like receptors). Dopamine agonists mimic the effects of the natural neurotransmitter and it has been found that selective dopamine D2 or D1 and mixed D1/D2 agonists are useful in the treatment of Parkinson disease. As D2 (but not D1) agonists have shown undesirable dyskinetic effects it is of highest interest to understand the reasons behind D1/D2 agonist selectivity. This thesis is focused on the identification of structural features that determine the selectivity of D1 and D2 receptor agonists for their respective receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor, and excluded volumes where no heavy atoms are permitted. The sets of D1 and D2 ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. 3D receptor models in their agonist bound state were also generated for dopamine D1 and D2, in order to get improved insight into agonist binding. The constructed D1 and D2 agonist pharmacophore models were superimposed into their corresponding receptor model. The arrangement of pharmacophoric features were in agreement with the position of the agonist key interacting amino acids in the binding site, with exception of one hydrogen bond accepting/donating feature in the D2 model and the positioning of the excluded volumes in both models. Both pharmacophore models were refined to better reflect the shape of the binding pocket and had similar pharmacophore hit rate when screening the test sets of dopamine ligands. Several key factors for D1/D2 agonist selectivity were identified. In addition, a semi-empirical method to model transmembrane proteins with focus on the ligand binding site has been developed. The method was evaluated by generating a β1-adrenergic receptor model which had an RMSD of 1.6 Å for all heavy atoms in the binding site relative the crystal structure. A D2 receptor model with an agonist present was constructed, but this model was unable to discriminate actives from inactives in a docking study.
Molecular Diversity, 2015
Homology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of β2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MOD-ELLER and ROSETTA programs. Top-ranked models have been validated with ligand docking simulations and in silico Alanine-scanning mutagenesis studies. The derived extracellular loop region of the protein models is directed toward the binding site cavity which is often involved in ligand binding. The binding sites of protein models were refined using induced fit docking to enable the side-chain refinement during ligand docking simulations. The derived models were then tested using molecular modeling techniques on several marketed drugs for schizophrenia. Alanine-scanning mutagenesis and molecular docking studies gave similar results for marketed drugs tested. We believe that these new D2 receptor models will be very useful for a better understand-Electronic supplementary material The online version of this article (
Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist
Science, 2010
Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.
Ligand discovery from a dopamine D3 receptor homology model and crystal structure
Nature Chemical Biology, 2011
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 has increased. Unfortunately, most GPCRs lack experimental structures. The determination of the D 3 receptor structure, and a community challenge 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 from 0.2 to 3.1μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities from 0.3 to 3.0μM. One of the novel ligands from the homology model screen was optimized for affinity to 81nM. The feasibility of docking screens against modeled GPCRs more generally is considered.
Journal of molecular modeling, 2016
In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalent antagonists. Our approach was based on protein-protein docking, applying the Rosetta software to obtain populations of dimers as present in membranes with all the main possible interfaces. Consensus scoring based on the values and frequencies of best interfaces regarding four scoring parameters, Rosetta interface score, interface area, free energy of binding and energy of hydrogen bond interactions indicated that the best scored dimer model possesses a TM4-TM5-TM7-TM1 interface, which is in agreement with experimental data. This model was used to study interactions of the previously publishe...