G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

Vignir Ísberg; Thomas Balle; Tommy Sander; Flemming Steen Jørgensen; David Erik Immanuel Gloriam

doi:10.1021/ci100402f

G protein- and agonist-bound serotonin 5-HT_2A receptor model activated by steered molecular dynamics simulations

Vignir Ísberg, Thomas Balle, Tommy Sander, Flemming Steen Jørgensen, David Erik Immanuel Gloriam

37 Citations (Scopus)

Abstract

A 5-HT_2A receptor model was constructed by homology modeling based on theβ₂-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT_2A receptor model was transferred into an active conformation by an agonist ligand and a G_αq peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT_2A receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.

Original language	English
Journal	Journal of Chemical Information and Modeling
Volume	51
Issue number	2
Pages (from-to)	315-325
ISSN	1549-9596
DOIs	https://doi.org/10.1021/ci100402f
Publication status	Published - 28 Feb 2011

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/ci100402f

Cite this

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title = "G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations",

abstract = "A 5-HT2A receptor model was constructed by homology modeling based on theβ2-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT2A receptor model was transferred into an active conformation by an agonist ligand and a Gαq peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT2A receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.",

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T1 - G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

AU - Ísberg, Vignir

AU - Balle, Thomas

AU - Sander, Tommy

AU - Jørgensen, Flemming Steen

AU - Gloriam, David Erik Immanuel

PY - 2011/2/28

Y1 - 2011/2/28

N2 - A 5-HT2A receptor model was constructed by homology modeling based on theβ2-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT2A receptor model was transferred into an active conformation by an agonist ligand and a Gαq peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT2A receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.

AB - A 5-HT2A receptor model was constructed by homology modeling based on theβ2-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT2A receptor model was transferred into an active conformation by an agonist ligand and a Gαq peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT2A receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.

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