Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors.
J Chem Inf Model
; 51(2): 420-33, 2011 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-21299232
ABSTRACT
Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions. (1) We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5-HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydro-pyrrolo[2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist- and antagonist-bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biologia Computacional
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Receptor 5-HT2B de Serotonina
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Receptor 5-HT2C de Serotonina
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Agonistas do Receptor 5-HT2 de Serotonina
/
Antagonistas do Receptor 5-HT2 de Serotonina
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos