Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors

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.