The dopamine D2 receptor dimer and its interaction with homobivalent antagonists

homology modeling, docking and molecular dynamics

Agnieszka A. Kaczor, Manuela Jorg, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article number203
Number of pages14
JournalJournal of Molecular Modeling
Volume22
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • Bivalent ligands
  • Dopamine D receptor
  • GPCR
  • GPCR dimer
  • Homology modeling
  • Molecular docking
  • Molecular dynamics

Cite this

@article{fbca51be51e74786bf59a114097564d2,
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.",
keywords = "Bivalent ligands, Dopamine D receptor, GPCR, GPCR dimer, Homology modeling, Molecular docking, Molecular dynamics",
author = "Kaczor, {Agnieszka A.} and Manuela Jorg and Ben Capuano",
year = "2016",
month = "9",
day = "1",
doi = "10.1007/s00894-016-3065-2",
language = "English",
volume = "22",
journal = "Journal of Molecular Modeling",
issn = "1610-2940",
publisher = "Springer-Verlag London Ltd.",
number = "9",

}

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists : homology modeling, docking and molecular dynamics. / Kaczor, Agnieszka A.; Jorg, Manuela; Capuano, Ben.

In: Journal of Molecular Modeling, Vol. 22, No. 9, 203, 01.09.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The dopamine D2 receptor dimer and its interaction with homobivalent antagonists

T2 - homology modeling, docking and molecular dynamics

AU - Kaczor, Agnieszka A.

AU - Jorg, Manuela

AU - Capuano, Ben

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - Bivalent ligands

KW - Dopamine D receptor

KW - GPCR

KW - GPCR dimer

KW - Homology modeling

KW - Molecular docking

KW - Molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=84982811760&partnerID=8YFLogxK

U2 - 10.1007/s00894-016-3065-2

DO - 10.1007/s00894-016-3065-2

M3 - Article

VL - 22

JO - Journal of Molecular Modeling

JF - Journal of Molecular Modeling

SN - 1610-2940

IS - 9

M1 - 203

ER -