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
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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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    ABSTRACT: Transporters are ubiquitous proteins mediating the translocation of solutes across cell membranes, a biological process involved in nutrition, signaling, neurotransmission, cell communication and drug uptake or efflux. Similarly to enzymes, most transporters have a single substrate binding-site and thus their activity follows Michaelis-Menten kinetics. Substrate binding elicits a series of structural changes, which produce a transporter conformer open toward the side opposite to the one from where the substrate was originally bound. This mechanism, involving alternate outward- and inward-facing transporter conformers, has gained significant support from structural, genetic, biochemical and biophysical approaches. Most transporters are specific for a given substrate or a group of substrates with similar chemical structure, but substrate specificity and/or affinity can vary dramatically, even among members of a transporter family that show high overall amino acid sequence and structural similarity. The current view is that transporter substrate affinity or specificity is determined by a small number of interactions a given solute can make within a specific binding site. However, genetic, biochemical and in silico modeling studies with the purine transporter UapA of the filamentous ascomycete Aspergillus nidulans have challenged this dogma. This review highlights results leading to a novel concept, stating that substrate specificity, but also transport kinetics and transporter turnover, are determined by subtle intramolecular interactions between a major substrate binding site and independent outward- or cytoplasmically-facing gating domains, analogous to those present in channels. This concept is supported by recent structural evidence from several, phylogenetically and functionally distinct transporter families. The significance of this concept is discussed in relationship to the role and potential exploitation of transporters in drug action.
    Frontiers in Pharmacology 09/2014; 5. DOI:10.3389/fphar.2014.00207 · 3.80 Impact Factor
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    • "The crystal structure for the bacterial homo-tetrameric voltage-gated Na+ channel from Arcobacter butzleri (NavAb) has been reported however, the structure for SCN5a has yet to be described and is expected to be very different from that of NavAb [34]. It is important to mention that issue of multiple receptors for existing drugs, while often ignored, is well known and represent significant challenge in targeted drug development [35]. "
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    ABSTRACT: One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4-S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs.
    PLoS ONE 09/2014; 9(9):e105553. DOI:10.1371/journal.pone.0105553 · 3.23 Impact Factor
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    • "Thus, differences in active transport in serum secretion protein-binding, metabolism, and pharmacological effects for both molecules may have differences for achieving the biophase. Such steroisomers frequently differ in terms of their biological activity and pharmacokinetic (PK) profiles and the use of such mixtures contributes to the adverse effects of the drug particularly if they are associated with the inactive or less active isomer [10, 11]. "
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    ABSTRACT: Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10 mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24 h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice.
    08/2013; 2013(1):392010. DOI:10.1155/2013/392010
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