New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors.

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Palmeira A, Rodrigues F, Sousa E, Pinto M, Vasconcelos MH, Fernandes MX

New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors.

Chem Biol Drug Des. 2011 Jul;78(1):57-72. doi: 10.1111/j.1747-0285.2011.01089.x. Epub 2011 Mar 29.

PubMed ID

21235729 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Hycanthone	P-glycoprotein 1	Protein	Humans	Yes	Inhibitor	Details