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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

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

A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-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(aq) 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.
OriginalsprogEngelsk
TidsskriftJournal of Chemical Information and Modeling
Vol/bind51
Udgave nummer2
Sider (fra-til)315-325
ISSN1549-9596
DOI
StatusUdgivet - 28 feb. 2011

ID: 33097003