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

摘要

The multidrug resistance (MDR) phenotype exhibited by cancer cells is be-lieved to be hampering successful chemotherapy treatment in cancer patients. A group of ABC drug transporters which particularly include P-glycoprotein (Pgp) con-tribute 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 data-base 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 com-pounds were found to significantly increase the accumulation of Rh 123, four were found to decrease and six showed only a slight effect on the accumulation of Rh 123. Furthermore, the competitive/non-competitive mechanism for the most promising compounds was determined by a luminescence Pgp's ATPase assay. Based on the cy-tometry 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.