Thesis supervisor: Katalin Goda
Location of studies (in Hungarian): University of Debrecen Abbreviation of location of studies: DEAOK
Description of the research topic:
The human ABCB1 (P-glycoprotein, Pgp) protein is an active exporter expressed in the plasma membrane of cells forming biological barriers. In accordance with its broad substrate spectrum and tissue expression pattern, it affects the pharmacokinetics of numerous chemotherapeutic drugs and it is involved in unwanted drug–drug interactions leading to side effects or toxicities. When expressed in tumor tissues, it contributes to the development of chemotherapy resistance in malignancies. Therefore, the understanding of the molecular details of the ligand–ABCB1 interactions is of crucial importance.
Polyphenols, such as flavonoids and anthocyanins are present in fruits and vegetables at high concentrations and often used in food supplements. Previous studies have shown that certain flavonoids and anthocyanins interact with human ABCB1, although the data obtained in different experimental systems are often controversial.
In the planned research we would like to elucidate the interactions of human ABCB1 with structurally diverse polyphenols abundant in red fruits. We study the effects of these compounds on the basal and verapamil-stimulated ATPase activity, transport activity as well as on the conformational response of ABCB1 measured in UIC2 reactivity tests. Since the complex substrate binding pocket of ABCB1 may accommodate more than one substrate simultaneously, we also would like to study the effects different combinations of polyphenols or polyphenols and other ABCB1 substrate drugs. To gain deeper insight into the molecular details of ligand–ABCB1 interactions, molecular docking experiments and molecular dynamics (MD) simulations are also planned.
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