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WIREs Comput Mol Sci
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About P‐glycoprotein: a new drugable domain is emerging from structural data

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P‐glycoprotein (P‐gp) has been considered an important molecular target in the reversal of multidrug resistance (MDR). As such, the development of P‐gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies for overcoming MDR. Since the identification of the P‐gp's role in MDR, several studies have been performed in order to develop effective P‐gp modulators and understand the efflux mechanism. However, no efflux modulator is still clinically available for treating multidrug‐resistant cancers. Nevertheless, recent experimental studies suggest that MDR can be surpassed by targeting a specific region within the ABC transporter structure rather than the polyspecific drug‐binding pocket. This article will focus on the information available about this new target region and on a brief overview of which scaffolds would be suitable for modulating P‐gp at this new location. WIREs Comput Mol Sci 2017, 7:e1316. doi: 10.1002/wcms.1316 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics
Historical timeline of P‐glycoprotein studies.
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Molecules found to bind P‐glycoprotein at the TMH–NBD interface. †, Experimental evidences; ‡, in silico predictions.
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(a) Phylogenetic tree for ABCB1 homologues; (b) Interaction scheme between coupling helices ICH1–ICH4 and nucleotide‐binding domains in P‐gp. Sequence alignments were obtained on the Clustal Omega web server (http://www.ebi.ac.uk/Tools/msa/clustalo/). DSSP secondary structure for both NBD1 and NBD2 was retrieved from the Protein Data Bank (PDB ID: 4Q9H).
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Conformations of the four intracellular helices (based on the crystallographic data retrieved from PDB ID: 4Q9H). ICH1/ICH4 interact with NBD1 and ICH2/ICH3 with NBD2.
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Molecules from the three generations of P‐gp inhibitors.
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The P‐gp architecture and location of the drug‐binding H, R, and M sites.
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