A. Bronowska et al., Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors, BIO MED CH, 9(4), 2001, pp. 881-895
Three-dimensional (3-D) models of the human serotonin 5-HT1A and 5-HT2A rec
eptors 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 a
mino acids in transmembrane helix (TMH) 2 and 7. while the main interaction
s of the ligand aromatic moieties were with amino acids in TMH5, 6 and 7. D
ifferences in binding site architecture in the region of highly conserved s
erine and tyrosine residues in TMH7 gave slightly different binding modes o
f the buspirone analogues at the 5-HT1A and 5-HT2A receptors. Molecular dyn
amics simulations of receptor-ligand interactions indicated that the buspir
one analogues did not alter the interhelical hydrogen bonding patterns upon
binding to the 5-HT2A receptor, while interhelical hydrogen bonds were bro
ken and others were formed upon ligand binding to the 5-HT1A receptor, The
ligand-induced changes in interhelical hydrogen bonding patterns of the 5-H
T1A receptor were followed by rigid body movements of TMH2, 4 and 6 relativ
e to each other and to the other TMHs, which may reflect the structural con
version into an active receptor structure. (C) 2001 Elsevier Science Ltd. A
ll rights reserved.