Pharmacophore-Based Screening as a Clue for the Discovery of New P-Glycoprotein Inhibitors

The multidrug resistance (MDR) phenotype exhibited by cancer cells is believed to be hampering successful chemotherapy treatment in cancer patients. A group of ABC drug transporters which particularly include P-glycoprotein (Pgp) contribute to this phenotype. Thus, there is a need to anticipate whether drug candidates are possible Pgp substrates or noncompetitive inhibitors. Therefore, a pharmacophore model was created based on known Pgp inhibitors and it was used to screen a database of commercial compounds. After the screening, twenty-one candidate compounds were selected and their influence in the intracellular accumulation of Pgp substrate Rhodamine-123 (Rh123) was investigated by flow cytometry. Eleven compounds were found to significantly increase the accumulation of Rh123, four were found to decrease and six showed only a slight effect on the accumulation of Rh123. Furthermore, the competitive/non-competitive mechanism for the most promising compounds was determined by a luminescence Pgp’s ATPase assay. Based on the cytometry results, a new pharmacophore was created for the Pgp inhibitory activity. The overall results provide important clues on how to proceed towards the discovery of Pgp inhibitors and which type of molecules merit further analysis.