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

作者：Palmeira Andreia; Rodrigues Freddy; Sousa Emilia; Pinto Madalena; Vasconcelos M Helena; Fernandes Miguel X^*

来源：Chemical Biology & Drug Design, 2011, 78(1): 57-72.

DOI：10.1111/j.1747-0285.2011.01089.x

• cancer
• multidrug-resistance transporters
• oxazepine
• P-glycoprotein inhibitors
• pharmacophore
• virtual screening

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.

• 出版日期2011-7