title: The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics.
abstract: 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 published dopamine D2 receptor homobivalent antagonists based on clozapine,1,4-disubstituted aromatic piperidines/piperazines and arylamidoalkyl substituted phenylpiperazine pharmacophores. It was found that the homobivalent antagonists stabilize the receptor-inactive conformation by maintaining the ionic lock interaction, and change the dimer interface by disrupting a set of hydrogen bonds and maintaining water- and ligand-mediated hydrogen bonds in the extracellular and intracellular part of the interface. Graphical Abstract Structure of the final model of the dopamine D2 receptor homodimer, indicating the distancebetween Tyr37 and Tyr 5.42 in the apo form (left) and in the complex with the ligand (right).
authors: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division for Medical Analytics, Medical University of Lublin, 4A Chodźki St., 20059, Lublin, Poland. agnieszka.kaczor@umlub.pl.|School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, 70211, Kuopio, Finland. agnieszka.kaczor@umlub.pl.
authors: Agnieszka A
authors: AA
authors: Kaczor
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors: Manuela
authors: M
authors: Jörg
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors: Ben
authors: B
authors: Capuano
mesh_terms: D001665:Binding Sites; D065127:Dopamine D2 Receptor Antagonists / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2
keywords: Bivalent ligands; Dopamine D2 receptor; GPCR; GPCR dimer; Homology modeling; Molecular docking; Molecular dynamics