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

• Type: Article in International Scientific Journal
• Date: 2011

Authors

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

Journal

Title: Chemical Biology and Drug Design

Vol. 78

Pages: 57-72

ISSN: 1747-0277

Publisher: Wiley-Blackwell

Indexing

ISI Proceedings

ISI Web of Knowledge - 51 Citations

Scopus - 55 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16