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Multidrug efflux pumps: drug binding – gates or cavity?
Author(s) -
Crowley Emily,
Callaghan Richard
Publication year - 2010
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07484.x
Subject(s) - drug , efflux , multiple drug resistance , mechanism (biology) , binding site , pharmacology , drug resistance , disease , drug discovery , plasma protein binding , atp binding cassette transporter , biology , medicine , bioinformatics , biochemistry , transporter , genetics , philosophy , epistemology , gene
The role of the ATP‐binding cassette ABCB1 in mediating the resistance to chemotherapy in many forms of cancer has been well established. The protein is also endogenously expressed in numerous barrier and excretory tissues, thereby regulating or impacting on drug pharmacokinetic profiles. Given these prominent roles in health and disease, a great deal of biochemical, structural and pharmacological research has been directed towards modulating its activity. Despite the effort, only a small handful of compounds have reached the later stages of clinical trials. What is responsible for this poor return on the heavy research investment? Perhaps the most significant factor is the lack of information on the location, physical features and chemical properties of the drug‐binding site(s) in ABCB1. This minireview outlines the various strategies and outcomes of research efforts to pin‐point the sites of interaction. The data may be assimilated into two working hypotheses to describe drug binding to ABCB1; (a) the central cavity and the (b) domain interface models.