Structural and functional aspects of P-glycoprotein and its inhibitors

Life Sci. 2018 Dec 1;214:118-123. doi: 10.1016/j.lfs.2018.10.048.

Shirin Mollazadeh ¹, Amirhossein Sahebkar ², Farzin Hadizadeh ³, Javad Behravan ⁴, Sepideh Arabzadeh ⁵

Affiliations

1 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
2 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
3 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: Hadizadehf@mums.ac.ir.
4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: Behravanj@mums.ac.ir.
5 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

PMID: 30449449 DOI: 10.1016/j.lfs.2018.10.048

Abstract

P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity has been the subject of numerous attempts to develop P-gp inhibitors. The aim of this review is to present up-to-date information on the structural and functional aspects of P-gp and its known inhibitors. The data presented also provide some information on drug discovery approaches for candidate P-gp inhibitors. Nucleotide-binding domains (NBDs) and drug-binding domains (DBDs) have been extensively studied to gain more information about P-gp inhibition and it looks that the ATPase activity of this pump has been the most attractive target for designing inhibitors. Hydrophobic and π-π (aromatic) interactions between P-gp binding domains and inhibitors are dominant intermolecular forces that have been reported in many studies using different methods. Many synthetic and Natural Products have been found to possess inhibitory or modulatory effects on drug transporter proteins. Log P value is an important factor in studying these inhibitors and has a crucial role on absorption, distribution, metabolism, and excretion (ADME) properties of candidate P-gp inhibitors.

Keywords

Drug transporter; Inhibitor; Multidrug resistance; P-glycoprotein.

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