Shape-based reprofiling of FDA-approved drugs for the H1 histamine receptor.
J Med Chem
; 55(16): 7054-60, 2012 Aug 23.
Article
em En
| MEDLINE
| ID: mdl-22793499
ABSTRACT
Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores Histamínicos H1
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Modelos Moleculares
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Bases de Dados de Compostos Químicos
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Antagonistas dos Receptores Histamínicos H1
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article