What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?
Pharmacol Rev
; 67(1): 198-213, 2015.
Article
em En
| MEDLINE
| ID: mdl-25527701
ABSTRACT
G protein-coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Receptores Acoplados a Proteínas G
/
Terapia de Alvo Molecular
/
Aminas
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Pharmacol Rev
Ano de publicação:
2015
Tipo de documento:
Article