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Publication
New uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitors
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Advisor(s)
Abstract(s)
P-glycoprotein (P-gp) is one of the best character ized transporters responsible for the multidrug
resistance phenotype exhibited by cancer cells.
Therefore, there is widespread interest in eluci dating whether existing drugs are candidate P-gp
substrates or inhibitors. With this aim, a pharma cophore 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 activ ity 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 tetracy clic antidepressant drugs, were discovered to be
potent non-competitive inhibitors of P-gp, causing
a 3.5-fold decrease in the doxorubicin GI50 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.
Description
Keywords
Cancer Multidrug-resistance transporters Oxazepine P-glycoprotein inhibitors Pharmacophore Virtual screening . Faculdade de Ciências Exatas e da Engenharia
Citation
Palmeira, A., Rodrigues, F., Sousa, E., Pinto, M., Vasconcelos, M. H., & Fernandes, M. X. (2011). New uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitors. Chemical biology & drug design, 78(1), 57-72.
Publisher
Wiley