Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor.
Angew Chem Int Ed Engl
; 55(30): 8661-5, 2016 07 18.
Article
em En
| MEDLINE
| ID: mdl-27244650
ABSTRACT
G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptor 5-HT1A de Serotonina
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
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