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      Prediction of drug–ABC-transporter interaction — Recent advances and future challenges☆

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          Abstract

          With the discovery of P-glycoprotein (P-gp), it became evident that ABC-transporters play a vital role in bioavailability and toxicity of drugs. They prevent intracellular accumulation of toxic compounds, which renders them a major defense mechanism against xenotoxic compounds. Their expression in cells of all major barriers (intestine, blood–brain barrier, blood–placenta barrier) as well as in metabolic organs (liver, kidney) also explains their influence on the ADMET properties of drugs and drug candidates. Thus, in silico models for the prediction of the probability of a compound to interact with P-gp or analogous transporters are of high value in the early phase of the drug discovery process. Within this review, we highlight recent developments in the area, with a special focus on the molecular basis of drug–transporter interaction. In addition, with the recent availability of X-ray structures of several ABC-transporters, also structure-based design methods have been applied and will be addressed.

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          Most cited references 72

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          Human ATP-binding cassette (ABC) transporter family

          There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC) transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx) or out (efflux) of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]). ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.
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            The ABC protein turned chloride channel whose failure causes cystic fibrosis.

            CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. New structural and biochemical information from prokaryotic ABC proteins and functional information from CFTR channels has led to a unifying mechanism explaining those ATP-driven conformational changes.
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              PubChem's BioAssay Database

              PubChem (http://pubchem.ncbi.nlm.nih.gov) is a public repository for biological activity data of small molecules and RNAi reagents. The mission of PubChem is to deliver free and easy access to all deposited data, and to provide intuitive data analysis tools. The PubChem BioAssay database currently contains 500 000 descriptions of assay protocols, covering 5000 protein targets, 30 000 gene targets and providing over 130 million bioactivity outcomes. PubChem's bioassay data are integrated into the NCBI Entrez information retrieval system, thus making PubChem data searchable and accessible by Entrez queries. Also, as a repository, PubChem constantly optimizes and develops its deposition system answering many demands of both high- and low-volume depositors. The PubChem information platform allows users to search, review and download bioassay description and data. The PubChem platform also enables researchers to collect, compare and analyze biological test results through web-based and programmatic tools. In this work, we provide an update for the PubChem BioAssay resource, including information content growth, data model extension and new developments of data submission, retrieval, analysis and download tools.
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                Author and article information

                Journal
                8710523
                21484
                Adv Drug Deliv Rev
                Adv. Drug Deliv. Rev.
                Advanced drug delivery reviews
                0169-409X
                1872-8294
                17 September 2018
                11 March 2015
                23 June 2015
                18 March 2019
                : 86
                : 17-26
                Affiliations
                University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Wien, Austria
                Author notes
                [* ]Corresponding author. Tel.: +43 1427755110. gerhard.f.ecker@ 123456univie.ac.at (G.F. Ecker).
                [☆]

                This review is part of the Advanced Drug Delivery Reviews theme issue on “ In silico ADMET predictions in pharmaceutical research”.

                Article
                EMS79551
                10.1016/j.addr.2015.03.001
                6422311
                25769815

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

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