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Abstract
P-glycoprotein (Pgp), a membrane-bound efflux protein and part of the 49-member ATP-Binding Cassette (ABC) transporter family, is well-known and vastly studied due to its role in conferring a phenomenon known as multidrug resistance (MDR) and for its heavy contribution in drug disposition. Claiming numerous FDA-approved therapeutics as substrates and subjecting them to its efflux often results in subtherapeutic efficacy. Despite decades of studies, there is still much yet to be understood about drug-Pgp interactions. Pgp’s natural role in the body is to act as a gatekeeper, protecting cells and tissues from toxins, and it is understandably expressed in many critical organs and barriers, such as the liver, kidneys, small intestine, and blood-brain barrier, among others. However, its vast promiscuity has proven a bane for the clinical setting. While many attempts have been made to inhibit its activity, these have been met predominantly with unsuccessful results. Considering Pgp’s vital role in the body, it is of interest to find ways to circumvent its activity, rather than inhibit it entirely. Such a daunting task requires in-depth analyses of the molecular interactions between therapeutics and Pgp – a mission that proves challenging with Pgp’s multiple proposed binding sites and a lack of full understanding of Pgp’s transport cycle coupled with ATP hydrolysis. This study focused on two classes of anti-cancer drugs, PARP inhibitors and anthracyclines, and their interactions with Pgp. Transport and binding studies, coupled with indirect conformational probing and investigation into the effects of each compound on Pgp’s ATPase activity allowed the development of an overall model of PARPi-Pgp interactions that provides insight for future drug design. Studies with anthracyclines are currently ongoing and are elucidating the differences within the class that drive Pgp-mediated transport of anthracyclines.