Binding Site Interactions of Modulators of Breast
Cancer Resistance Protein, Multidrug Resistance-Associated Protein
2, and P‑Glycoprotein Activity
Posted on 2020-06-18 - 13:33
ATP-binding cassette (ABC)-transporters
protect tissues by pumping
their substrates out of the cells in many physiological barriers,
such as the blood–brain barrier, intestine, liver, and kidney.
These substrates include various endogenous metabolites, but, in addition,
ABC transporters recognize a wide range of compounds, therefore affecting
the disposition and elimination of clinically used drugs and their
metabolites. Although numerous ABC-transporter inhibitors are known,
the underlying mechanism of inhibition is not well characterized.
The aim of this study is to deepen our understanding of transporter
inhibition by studying the molecular basis of ligand recognition.
In the current work, we compared the effect of 44 compounds on the
active transport mediated by three ABC transporters: breast cancer
resistance protein (BCRP and ABCG2), multidrug-resistance associated
protein (MRP2 and ABCC2), and P-glycoprotein (P-gp and ABCB1). Eight
compounds were strong inhibitors of all three transporters, while
the activity of 36 compounds was transporter-specific. Of the tested
compounds, 39, 25, and 11 were considered as strong inhibitors, while
1, 4, and 11 compounds were inactive against BCRP, MRP2, and P-gp,
respectively. In addition, six transport-enhancing stimulators were
observed for P-gp. In order to understand the observed selectivity,
we compared the surface properties of binding cavities in the transporters
and performed structure–activity analysis and computational
docking of the compounds to known binding sites in the transmembrane
domains and nucleotide-binding domains. Based on the results, the
studied compounds are more likely to interact with the transmembrane
domain than the nucleotide-binding domain. Additionally, the surface
properties of the substrate binding site in the transmembrane domains
of the three transporters were in line with the observed selectivity.
Because of the high activity toward BCRP, we lacked the dynamic range
needed to draw conclusions on favorable interactions; however, we
identified amino acids in both P-gp and MRP2 that appear to be important
for ligand recognition.
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Deng, Feng; Ghemtio, Leo; Grazhdankin, Evgeni; Wipf, Peter; Xhaard, Henri; Kidron, Heidi (2020). Binding Site Interactions of Modulators of Breast
Cancer Resistance Protein, Multidrug Resistance-Associated Protein
2, and P‑Glycoprotein Activity. ACS Publications. Collection. https://doi.org/10.1021/acs.molpharmaceut.0c00155