The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: What we (need to) know and how we can do so

School of Chemistry, The University of Manchester, 131 Princess St, Manchester M1 7DN, UK
Drug discovery today (Impact Factor: 6.69). 11/2012; 18(5-6). DOI: 10.1016/j.drudis.2012.11.008
Source: PubMed


A recent paper in this journal sought to counter evidence for the role of transport proteins in affecting drug uptake into cells, and questions that transporters can recognize drug molecules in addition to their endogenous substrates. However, there is abundant evidence that both drugs and proteins are highly promiscuous. Most proteins bind to many drugs and most drugs bind to multiple proteins (on average more than six), including transporters (mutations in these can determine resistance); most drugs are known to recognise at least one transporter. In this response, we alert readers to the relevant evidence that exists or is required. This needs to be acquired in cells that contain the relevant proteins, and we highlight an experimental system for simultaneous genome-wide assessment of carrier-mediated uptake in a eukaryotic cell (yeast).

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Available from: Elizabeth Bilsland, Apr 02, 2014
    • "and can be used to evaluate and identify the contribution of carrier-mediated systems including those with high capacity, by assessing the concentration-dependence of the transport using drug concentrations high enough to surpass the Km of the transporter (Kell et al., 2013). Our results show that the transport of clonidine and DPH at the mouse BRB involves a common carrier-mediated system functionally identified as a sodium-independent proton/drug-antiporter, in addition to a relative minor passive diffusion component. "
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    British Journal of Pharmacology 07/2015; 172(19). DOI:10.1111/bph.13246 · 4.84 Impact Factor
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    • "However, still most antifungal, antiprotozoan or anticancer drugs used today have not been designed to distinguish between the transporters of target and non-target cells and thus may be taken up non-specifically. Some present day drugs do not need to cross the plasma membrane to act, but rather target essential plasma membrane components , basically transporters, channels or receptors (Hamman et al., 2007; Kell et al., 2013). Transporters, being the most abundant of these classes of transmembrane proteins, constitute a promising target for specific drug action. "
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    Frontiers in Pharmacology 09/2014; 5. DOI:10.3389/fphar.2014.00207 · 3.80 Impact Factor
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    PLoS ONE 09/2014; 9(9):e105553. DOI:10.1371/journal.pone.0105553 · 3.23 Impact Factor
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