Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.

We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.

[1]  R. E. Salmas,et al.  Investigation of Inhibition Mechanism of Chemokine Receptor CCR5 by Micro-second Molecular Dynamics Simulations , 2015, Scientific Reports.

[2]  R. E. Salmas,et al.  Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions , 2015, Molecular Diversity.

[3]  Serdar Durdagi,et al.  Elucidation of Conformational States, Dynamics, and Mechanism of Binding in Human κ-Opioid Receptor Complexes , 2014, J. Chem. Inf. Model..

[4]  G. Liapakis,et al.  The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: a concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives. , 2012, European journal of medicinal chemistry.

[5]  R. Böckmann,et al.  Optimization of the OPLS-AA Force Field for Long Hydrocarbons. , 2012, Journal of chemical theory and computation.

[6]  Albert C. Pan,et al.  Activation mechanism of the β2-adrenergic receptor , 2011, Proceedings of the National Academy of Sciences.

[7]  S. Rasmussen,et al.  Crystal Structure of the β2Adrenergic Receptor-Gs protein complex , 2011, Nature.

[8]  Cheng Zhang,et al.  Structure and Function of an Irreversible Agonist-β2 Adrenoceptor complex , 2010, Nature.

[9]  P. Fletcher,et al.  Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization , 2010, Molecular Brain.

[10]  S. Durdağı,et al.  A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling, docking, de novo drug design and molecular dynamics analysis , 2010, Molecular Diversity.

[11]  Irina S. Moreira,et al.  Allosteric communication between protomers of dopamine Class A GPCR dimers modulates activation , 2009, Nature chemical biology.

[12]  Serdar Durdagi,et al.  Antihypertensive Drug Valsartan in Solution and at the AT1 Receptor: Conformational Analysis, Dynamic NMR Spectroscopy, in Silico Docking, and Molecular Dynamics Simulations , 2009, J. Chem. Inf. Model..

[13]  Jan H. Jensen,et al.  Very fast prediction and rationalization of pKa values for protein–ligand complexes , 2008, Proteins.

[14]  R. Stevens,et al.  A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. , 2008, Structure.

[15]  Rhiju Das,et al.  Macromolecular modeling with rosetta. , 2008, Annual review of biochemistry.

[16]  P. Seeman.  Antiparkinson therapeutic potencies correlate with their affinities at dopamine D2High receptors , 2007, Synapse.

[17]  Ben M. Webb,et al.  Comparative Protein Structure Modeling Using MODELLER , 2007, Current protocols in protein science.

[18]  Serdar Durdagi,et al.  The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2. , 2007, Journal of medicinal chemistry.

[19]  L. Guruprasad,et al.  Docking of phosphonate and trehalose analog inhibitors into M. tuberculosis mycolyltransferase Ag85C: Comparison of the two scoring fitness functions GoldScore and ChemScore, in the GOLD software , 2007, Bioinformation.

[20]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[21]  Johannes Schwarz,et al.  Psychosis pathways converge via D2High dopamine receptors , 2006, Synapse.

[22]  R. Friesner,et al.  New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies. , 2006, Bioorganic & medicinal chemistry.

[23]  Krzysztof Palczewski,et al.  Structure of the rhodopsin dimer: a working model for G-protein-coupled receptors. , 2006, Current opinion in structural biology.

[24]  P. Strange,et al.  Mechanisms of inverse agonist action at D2 dopamine receptors , 2005, British journal of pharmacology.

[25]  Philip Seeman,et al.  Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Seeman,et al.  Dopamine displaces [3H]domperidone from high‐affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography , 2003, Synapse.

[27]  Richard D. Taylor,et al.  Improved protein–ligand docking using GOLD , 2003, Proteins.

[28]  B. O'dowd,et al.  D2 dopamine receptor homodimerization is mediated by multiple sites of interaction, including an intermolecular interaction involving transmembrane domain 4. , 2003, Biochemistry.

[29]  Lei Shi,et al.  The Fourth Transmembrane Segment Forms the Interface of the Dopamine D2 Receptor Homodimer* , 2003, The Journal of Biological Chemistry.

[30]  A. Engel,et al.  Atomic-force microscopy: Rhodopsin dimers in native disc membranes , 2003, Nature.

[31]  P. Strange,et al.  Dopamine D2 Receptor Dimer Formation , 2001, The Journal of Biological Chemistry.

[32]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .

[33]  P. Seeman,et al.  Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand. , 1995, European journal of pharmacology.

[34]  M. Klein,et al.  Constant pressure molecular dynamics algorithms , 1994 .

[35]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[36]  P. Strange,et al.  Differences in the Ligand Binding Properties of the Short and Long Versions of the D2 Dopamine Receptor , 1993, Journal of neurochemistry.

[37]  J. Nilsson,et al.  Dopamine D2 receptor binding sites for agonists. A tetrahedral model. , 1985, Molecular pharmacology.

[38]  P. Seeman,et al.  The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form. , 1985, Endocrinology.

[39]  D. Sibley,et al.  Dopaminergic inhibition of adenylate cyclase correlates with high affinity agonist binding to anterior pituitary D2 dopamine receptors , 1984, Molecular and Cellular Endocrinology.

[40]  J. W. Wells,et al.  Dopamine Receptor Parameters Detected by [3H]Spiperone Depend on Tissue Concentration: Analysis and Examples , 1984, Journal of neurochemistry.

[41]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.