New Uses for Old Drugs: Pharmacophore-Based Screening for the Discovery of P-Glycoprotein Inhibitors

• Tipo: Artigo em Revista Científica Internacional
• Data: 2011

Autores

Andreia Palmeira (Autor) Outra; Freddy Rodrigues (Autor) Outra; Emilia Sousa (Autor) FFUP; Madalena Pinto (Autor) FFUP; Helena H Vasconcelos (Autor) FFUP; Miguel X Fernandes (Autor) Outra

Revista

Título: Chemical Biology and Drug Design

Vol. 78

Páginas: 57-72

ISSN: 1747-0277

Editora: Wiley-Blackwell

Indexação

ISI Proceedings

ISI Web of Knowledge - 51 Citações

Scopus - 55 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-002-Q18

DOI: 10.1111/j.1747-0285.2011.01089.x

Abstract (EN): P-glycoprotein (P-gp) is one of the best characterized transporters responsible for the multidrug resistance phenotype exhibited by cancer cells. Therefore, there is widespread interest in elucidating whether existing drugs are candidate P-gp substrates or inhibitors. With this aim, a pharmacophore model was created based on known P-gp inhibitors and it was used to screen a database of existing drugs. The P-gp modulatory activity of the best hits was evaluated by several methods such as the rhodamine-123 accumulation assay using K562Dox cell line, and a P-gp ATPase activity assay. The ability of these compounds to enhance the cytotoxicity of doxorubicin was assessed with the sulphorhodamine-B assay. Of the 21 hit compounds selected in silico, 12 were found to significantly increase the intracellular accumulation of Rhodamine-123, a P-gp substrate. In addition, amoxapine and loxapine, two tetracyclic antidepressant drugs, were discovered to be potent non-competitive inhibitors of P-gp, causing a 3.5-fold decrease in the doxorubicin GI(50) in K562Dox cell line. The overall results provide important clues for the non-label use of known drugs as inhibitors of P-gp. Potent inhibitors with a dibenzoxazepine scaffold emerged from this study and they will be further investigated in order to develop new P-gp inhibitors.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 16