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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Chemical Information and Modeling
Vol/bind	51
Udgave nummer	2
Sider (fra-til)	315-325
ISSN	1549-9596
DOI	https://doi.org/10.1021/ci100402f
Status	Udgivet - 28 feb. 2011

Emneord

Det tidligere Farmaceutiske Fakultet

Adgang til dokumentet

10.1021/ci100402f

Citationsformater

@article{12f9037bacca430ebe1b820cbf56e848,

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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Vignir {\'I}sberg and Thomas Balle and Tommy Sander and J{\o}rgensen, {Flemming Steen} and Gloriam, {David Erik Immanuel}",

year = "2011",

month = feb,

day = "28",

doi = "10.1021/ci100402f",

language = "English",

volume = "51",

pages = "315--325",

journal = "Journal of Chemical Information and Modeling",

issn = "1549-9596",

publisher = "American Chemical Society",

number = "2",

}

TY - JOUR

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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/ci100402f

DO - 10.1021/ci100402f

M3 - Journal article

C2 - 21261291

SN - 1549-9596

VL - 51

SP - 315

EP - 325

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 2

ER -