In Silico and In Vitro Drug Screening for Novel Inhibitors of Human MDR1 P‐Glycoprotein

Abstract

Cancer chemotherapy failures often involve the over‐expression of ABC‐transporters like the MDR1 P‐glycoprotein (Pgp). These membrane transporters use ATP hydrolysis to move a wide variety of compounds including cytotoxins across the plasma membrane, a normally protective function for the cell. In chemotherapies, however, selection for cells over‐expressing transporters like Pgp results in cell populations that are resistant to the therapeutic agents. This results in cancer recurrence that is multidrug resistant and refractory to treatment. In recent work using targeted molecular dynamics methods, we uncovered some of the molecular details of the conformational changes Pgp undergoes during its catalytic transport mechanism (Biochemistry 2012 51:5125–41). The conformational changes elucidated in this study have been used in massively parallel in silico ligand docking studies employing a very large database of commercially‐available compounds (zinc.docking.org). Using novel screening procedures, we have been able to identify several compounds that differentially bind to ATP hydrolyzing power transducing structures and not to drug transporting structures within Pgp. These compounds are predicted to be effective inhibitors of Pgp. In vitro analysis of several of the identified leads demonstrated that a number of these compounds do inhibit Pgp. Supported by NIH 1R15GM094771–01A1 to PDV and JGW.