Transporters as Drug Targets

Gerhard F. Ecker, Rasmus P. Clausen, Harald H. Sitte, Gerhard F. Ecker, Rasmus P. Clausen, Harald H. Sitte, Raimund Mannhold, Gerd Folkers, Helmut Buschmann

• Publisher: Wiley-VCH
• Year: 2016
• Print ISBN:
  9783527333844
• eBook ISBN:
  9783527679522
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

As opposed to other books on the topic, this volume is unique in also covering emerging transporter targets.
Following a general introduction to the importance of targeting transporter proteins with drugs, the book systematically presents individual transporter classes and explains their pharmacology and physiology. The text covers all transporter families with known or suspected importance as drug targets, including neurotransmitter transporters, ABC transporters, glucose transporters and organic ion transporters. The final part discusses recent advances in structural studies of transport proteins, assay methods for transport activity, and the systems biology of transporters and their regulation.
With its focus on drug development issues, this authoritative overview is required reading for researchers in industry and academia targeting transport proteins for the treatment of disease.

1
Insights into Transporter Classifications: an Outline of Transporters as Drug Targets

Michael Viereck,¹ Anna Gaulton,² and Daniela Digles¹

¹University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria

²EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK

1.1 Introduction

Classifications are a useful tool to get an overview of a topic. They show instances grouped together that share common properties according to the creator of the classification, and as in the case of hierarchical classifications, they allow to draw conclusions on the relation of different classes. In the case of the identification of drug targets (including transporters as the main drug target), several publications show classifications as a helpful tool.

Imming et al. [1] categorized drugs according to their targets, to get an estimate on the number of known drug targets, including channels and transporters. Drugs on the market were connected to a target only if it was described as the main target in the literature. For transport proteins (including uniporters, symporters, and antiporters), this identified six different types of transporter groups that are relevant as drug targets. These are the cation-chloride cotransporter (CCC) family (SLC 12), Na⁺/H⁺ antiporters (SLC 9), proton pumps, Na⁺/K⁺ ATPases, the eukaryotic (putative) sterol transporter (EST) family, and the neurotransmitter/Na⁺ symporter (NSS) family (SLC 6). These families mainly belong to either ATPases or solute carriers (SLC). Whether the EST family is treated as transport protein or not depends on the classification used.

Rask-Andersen et al. [2] used a manually curated and extended version of the DrugBank [3] data from 2009 to analyze drug targets. They identified 435 therapeutic effect-mediating targets, where the third largest group (67) is of transporter proteins (including 35 ion channels). These transport proteins are mainly targeted by antihypertensive drugs, diuretics, anaesthetics, and antiarrhythmic drugs. In a more recent study [4], they analyzed the Drugs in the Clinical Trials Database by CenterWatch to investigate the targets of new drug candidates. Transporter proteins in this data set were classified using the transporter classification (TC) system established by Saier et al. [5].

This chapter will first give an overview on selected existing transporter classifications and then describe our process of creating a combined classification scheme for the ChEMBL [6] database. Finally, the investigation of the counts of drugs and diseases for one example protein superfamily is provided, to show the usefulness of classifications in characterizing related proteins and to give a first overview on the topic of this book, focusing on transporters as drug targets.

1.2 Available Transporter Classifications

As a consequence of the significance of the transport process for every living organism, already numerous classification schemes for membrane transport proteins of several organisms exist. Quite a few focus only on specific families, for instance, the SLC superfamily or the ABC transporter superfamily. Table 1.1 shows a selection of membrane transport protein databases with a focus on human proteins. To keep the table concise, databases focusing on different organisms (e.g., the plant membrane protein database Aramemnon [7], the yeast transport protein database YTPdb [8], or ABCdb [9], a database about bacterial ABC systems) are not included, even though bacterial or protozoal channels and transporters can also be promising drug targets [10,11].

Table 1.1 Selection of transporter collections with a focus on human membrane transport proteins.

Database	Description	URL	Included proteins	Limited to organisms
Bioparadigms SLC Series [12]	Online resource of the 52 human solute carrier families	slc.bioparadigms.org/	Solute carriers	Homo sapiens
ChEMBL [6]	Large-scale bioactivity database for drug discovery	https://www.ebi.ac.uk/chembldb/target/browser	Proteins with bioactivity data	—
Human ABC transporters [13]	Basic information about human ABC transporters	www.nutrigene....

Table of contents

• Cover
• Methods and Principles in Medicinal Chemistry
• Title Page
• Copyright
• Preface
• A Personal Foreword
• Chapter 1: Insights into Transporter Classifications: an Outline of Transporters as Drug Targets
• Chapter 2: New Trends in Antidepressant Drug Research
• Chapter 3: The Molecular Basis of the Interaction Between Drugs and Neurotransmitter Transporters
• Chapter 4: γ-Aminobutyric Acid and Glycine Neurotransmitter Transporters
• Chapter 5: ABC Transporters: From Targets to Antitargets and Back
• Chapter 6: ABC Transporters Involved in Cholestasis
• Chapter 7: Recent Advances in Structural Modeling of ABC Transporters
• Chapter 8: PET Imaging of ABC Transporters at the Blood–Brain Barrier
• Chapter 9: The Systems Biology of Transporters – Targeting the Regulatory System for Transporters (FXR/RXR)
• Chapter 10: ANO1 as a Novel Drug Target
• Chapter 11: Ligand Discovery for the Nutrient Transporters ASCT2 and LAT-1 from Homology Modeling and Virtual Screening
• Chapter 12: Organic Anion Transporting Polypeptides as Drug Targets
• Index
• End User License Agreement