New Uses for Old Drugs: Pharmacophore‐Based Screening for the Discovery of P‐Glycoprotein Inhibitors
書誌事項
- 公開日
- 2011-03-29
- 権利情報
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- http://onlinelibrary.wiley.com/termsAndConditions#vor
- DOI
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- 10.1111/j.1747-0285.2011.01089.x
- 公開者
- Wiley
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説明
<jats:p>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<jats:italic>in silico</jats:italic>, 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<jats:sub>50</jats:sub>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.</jats:p>
収録刊行物
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- Chemical Biology & Drug Design
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Chemical Biology & Drug Design 78 (1), 57-72, 2011-03-29
Wiley