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- New uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitorsPublication . Palmeira, Andreia; Rodrigues, Freddy; Sousa, Emília; Pinto, Madalena; Vasconcelos, M. Helena; Fernandes, Miguel X.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.
- Structure and ligand-based design of P-glycoprotein inhibitors: a historical perspectivePublication . Palmeira, Andreia; Sousa, Emilia; Vasconcelos, M. Helena; Pinto, Madalena; Fernandes, Miguel X.Computer-assisted drug design (CADD) is a valuable approach for the discovery of new chemical entities in the field of cancer therapy. There is a pressing need to design and develop new, selective, and safe drugs for the treatment of multidrug resistance (MDR) cancer forms, specifically active against P-glycoprotein (P-gp). Recently, a crystallographic structure for mouse P-gp was obtained. However, for decades the design of new P-gp inhibitors employed mainly ligand-based approaches (SAR, QSAR, 3D-QSAR and phar macophore studies), and structure-based studies used P-gp homology models. However, some of those results are still the pillars used as a starting point for the design of potential P-gp inhibitors. Here, pharmacophore mapping, (Q)SAR, 3D-QSAR and homology modeling, for the discovery of P-gp inhibitors are reviewed. The importance of these methods for understanding mechanisms of drug resistance at a molecular level, and design P-gp inhibitors drug candidates are discussed. The examples mentioned in the review could provide insights into the wide range of possibilities of using CADD methodologies for the discovery of efficient P-gp inhibitors.