title: Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors.
abstract: Three-dimensional (3-D) models of the human serotonin 5-HT1A and 5-HT2A receptors were constructed, energy refined, and used to study the interactions with a series of buspirone analogues. For both receptors, the calculations showed that the main interactions of the ligand imide moieties were with amino acids in transmembrane helix (TMH) 2 and 7, while the main interactions of the ligand aromatic moieties were with amino acids in TMH5, 6 and 7. Differences in binding site architecture in the region of highly conserved serine and tyrosine residues in TMH7 gave slightly different binding modes of the buspirone analogues at the 5-HT1A and 5-HT2A receptors. Molecular dynamics simulations of receptor-ligand interactions indicated that the buspirone analogues did not alter the interhelical hydrogen bonding patterns upon binding to the 5-HT2A receptor, while interhelical hydrogen bonds were broken and others were formed upon ligand binding to the 5-HT1A receptor. The ligand-induced changes in interhelical hydrogen bonding patterns of the 5-HT1A receptor were followed by rigid body movements of TMH2, 4 and 6 relative to each other and to the other TMHs, which may reflect the structural conversion into an active receptor structure.
authors.affiliation: Department of Chemistry, University of Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Bronowska
authors.forename: A
authors.initials: A
authors.lastname: Leś
authors.forename: Z
authors.initials: Z
authors.lastname: Chilmonczyk
authors.forename: S
authors.initials: S
authors.lastname: Filipek
authors.forename: O
authors.initials: O
authors.lastname: Edvardsen
authors.forename: R
authors.initials: R
authors.lastname: Ostensen
authors.forename: I
authors.initials: I
authors.lastname: Sylte
mesh_terms: D002065:Buspirone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1
chemical_list: D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D002065:Buspirone