title: Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking.
abstract: Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2HighR and D2LowR dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2HighR and D2LowR targets were -12.04 and -9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2HighR and D2LowR with binding affinities (Ki) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [3H]domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2LowR. Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models.
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.
authors.forename: Ramin Ekhteiari
authors.identifier: 0000-0003-3888-5070
authors.initials: RE
authors.lastname: Salmas
authors.affiliation: Departments of Pharmacology and Psychiatry, University of Toronto , 260 Heath Street West, Unit 605, Toronto, Ontario M5P 3L6, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.
authors.forename: Busecan
authors.initials: B
authors.lastname: Aksoydan
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.|Department of Chemistry, Gebze Technical University , 41400, Kocaeli, Turkey.
authors.forename: Ismail
authors.identifier: 0000-0001-8256-6283
authors.initials: I
authors.lastname: Erol
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.
authors.forename: Isik
authors.initials: I
authors.lastname: Kantarcioglu
authors.affiliation: Max-Planck Institute for Dynamics of Complex Technical Systems , Molecular Simulations and Design Group, Sandtorstrasse 1, 39106 Magdeburg, Germany.
authors.forename: Matthias
authors.identifier: 0000-0001-7793-0052
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Chemistry, Istanbul Technical University , 34469 Istanbul, Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Yurtsever
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.
authors.forename: Serdar
authors.identifier: 0000-0002-0426-0905
authors.initials: S
authors.lastname: Durdagi
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D003499:Cyclic S-Oxides / Q000737:chemistry*; D018491:Dopamine Agonists / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017448:Receptors, Dopamine D2 / Q000737:chemistry*
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2
keywords: Antipsychotics; Dopamine D2 receptor; E-Pharmacophore modeling; Ensemble docking; LY404,039; MM/PBSA; Molecular dynamics (MD) simulations; Molecular modeling; Schizophrenia