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Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, G. Folkers, H. Buschmann
Editorial Board
J. Holenz, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, John Bondo Hansen

Previous Volumes of this Series:

Martic-Kehl, M. I., Schubiger, P.A. (Eds.)

Animal Models for Human Cancer

Discovery and Development of Novel Therapeutics


ISBN: 978-3-527-33997-6 Vol. 69

Holenz, Jörg (Ed.)

Lead Generation

Methods and Strategies


ISBN: 978-3-527-33329-5 Vol. 68

Erlanson, Daniel A./Jahnke, Wolfgang (Eds.)

Fragment-based Drug Discovery

Lessons and Outlook


ISBN: 978-3-527-33775-0 Vol. 67

Urbán, László/Patel, Vinod F./Vaz, Roy J. (Eds.)

Antitargets and Drug Safety


ISBN: 978-3-527-33511-4 Vol. 66

Keserü, György M./Swinney, David C. (Eds.)

Kinetics and Thermodynamics of Drug Binding


ISBN: 978-3-527-33582-4 Vol. 65

Pfannkuch, Friedlieb/Suter-Dick, Laura (Eds.)

Predictive Toxicology

From Vision to Reality


ISBN: 978-3-527-33608-1 Vol. 64

Kirchmair, Johannes (Ed.)

Drug Metabolism Prediction


ISBN: 978-3-527-33566-4 Vol. 63

Vela, José Miguel/Maldonado, Rafael/Hamon, Michel (Eds.)

In vivo Models for Drug Discovery


ISBN: 978-3-527-33328-8 Vol. 62

Liras, Spiros/Bell, Andrew S. (Eds.)

Phosphodiesterases and Their Inhibitors


ISBN: 978-3-527-33219-9 Vol. 61

Hanessian, Stephen (Ed.)

Natural Products in Medicinal Chemistry


ISBN: 978-3-527-33218-2 Vol. 60

Lackey, Karen/Roth, Bruce (Eds.)

Medicinal Chemistry Approaches to Personalized Medicine


ISBN: 978-3-527-33394-3 Vol. 59

Edited by Gerhard F. Ecker,
Rasmus P. Clausen, and Harald H. Sitte

Transporters as Drug Targets

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Drug transport across biological membranes fundamentally influences both the biological activity as well as the ADMET (absorption, distribution, metabolism, excretion, toxicity) properties of all small molecules. Therefore, transport proteins represent an eminent class of drug targets and ADMET-associated genes. Besides passive diffusion, transmembrane transport proteins play a pivotal role in the translocation of compounds, both across cellular membranes and physiological barriers. Passive and active transport across membranes is a pivotal process in all living species [1]. It allows a continuous communication of neighboring cells with simultaneous separation of compartments: channels and transmembrane transporters facilitate the active translocation of materials across membranes. Being embedded in the lipid bilayer, those specialized proteins turn the cell membrane into a selective “filter” [2].

About 800 human membrane transport proteins (including channels and transporters) are currently well characterized and for about 10% (approx. 2000) of all human genes a relation to transport is estimated. The gene families encode proteins transporting substrates that range from ions to sugars, amino acids, biogenic amines, lipids, and both hydrophilic and lipophilic xenobiotics. Membrane transport proteins are of interest as potential drug targets, for drug delivery, and as a cause of side effects and drug–drug interactions [2].

Drug transporters are multispecific transmembrane proteins that facilitate the membrane passage of most drugs. Drug transporters have a distinct expression pattern in the human body lining pharmacological barrier tissues, most importantly the small intestinal epithelium, the endothelial cells in the blood–brain barrier, the epithelium of the proximal tubule cells in the kidney, and hepatocytes in the liver [3]. Membrane transporters play a central role in the pathology of many diseases and have been acknowledged as one of the major protein classes to be targeted in future drug development. Thus, they are considered important as potential drug targets or antitargets for drug delivery and for drug–drug interactions.

With the increasing knowledge on their importance, regulatory bodies also started to request studies on drug–transporter interaction for selected transporter. However, the process of drug transport is quite complex, which renders the whole issue quite challenging [1].

The present volume focuses on transporters as drug targets themselves; it perfectly completes a former volume in this series on “Transporters as drug carriers,” with the focus on drug delivery and disposition [4]. The book will not provide a comprehensive overview of the wide field of drug transporters and their impact on the current drug discovery and development field, but will focus on some of the more relevant and well-established transporter drug targets. The first chapter provides insights into transporter classifications to get an overview about a topic. The classification scheme shows instances grouped together that share common properties according to the creator of the classification, and as in the case of hierarchical classifications they allow conclusions on the relation of different classes.

As a relevant example of well-established transporter drug targets a chapter of new trends in antidepressant drug research is presented, followed by a chapter discussing the molecular basis of the interaction between drugs and neurotransmitter transporters. Another chapter is focussing on γ-aminobutyric acid and glycine neurotransmitter transporters. There is strong evidence that ATP-binding cassette (ABC) transporters play a critical role in the pharmacokinetic and pharmacodynamic properties of many drugs and xenobiotics. ATP-binding cassette (ABC) transporters are membrane proteins that use the energy provided by ATP hydrolysis to translocate a wide variety of molecules, ranging from ions to macromolecules, across biological membranes. The importance and relevance of ABC transporters is covered by four book chapters. “ABC-Transporters – From targets to antitargets and back” is providing a general overview of the ABC transporter system and is followed by a chapter showing the role of the ABC transporter exemplarily in the therapeutic indication of cholestasis. The structure-based transporter research is described in the chapter “Recent Advances in Structural Modeling of ABC Transporters.” The growing importance of imaging methods in drug development is provided in the chapter “PET imaging of ABC transporters at the blood–brain barrier.”

In addition, some of the new promising transporters along with the structure-based information are presented as well covering “The Systems Biology of Transporters – Targeting the Regulatory System for Transporters (FXR, RXR),” “ANO1 as a novel drug target,” “Ligand discovery for the nutrient transporters ASCT2 and LAT-1 from homology modeling and virtual screening” as well as the emerging role of “Organic Anion Transporting Polypeptides as Drug Targets.”

We are grateful to Gerhard F. Ecker, Rasmus P. Clausen, and Harald H. Sitte for organizing this important volume and to work with such excellent authors. Last, but not least we thank Frank Weinreich and Waltraud Wüst from Wiley-VCH for their valuable contributions to this project and to the entire book series.

October 2016
Raimund Mannhold
Gerd Folkers
Helmut Buschmann


  1. 1 Ecker, G.F. (2014) Transmembrane drug transporter – taxonomy, assays, and their role in drug discovery. Drug. Discov. Today Technol., 12, e35–e36.
  2. 2 Viereck, M., Gaulton, A., Digles, D., and Ecker, G.F. (2014) Transporter taxonomy – a comparison of different transport protein classification schemes. Drug. Discov. Today Technol., 12, e37–e46.
  3. 3 Márton, J. and Krajcsi, P. (2014) In vitro methods in drug transporter interaction assessment. Drug. Discov. Today Technol., 12, e105–e112.
  4. 4 Ecker, F. and Chiba, P. (2010) Transporters as drug carriers: structure, function, substrates, vol. 44, Methods and Principles in Medicinal Chemistry, Series Editors: R. Mannhold, H. Kubinyi, and G. Folkers, Wiley-VCH.

A Personal Foreword

The generation of shielded compartments by phospholipid bilayers is of fundamental importance for the separation of internal and external milieus and, thus, for preserving the cell integrity. Owing to its hydrophobic nature, the lipid barrier imposes constraints on the movement of solutes, but it does not provide a completely impermeable barrier. Accordingly, cells have evolved mechanisms to selectively accumulate individual compounds or to preclude entry of xenobiotic or toxic compounds. This is, in general, achieved by a great variety of transmembrane transporters (TMTs). A genomic survey shows that there are more than 400 gene families, which encode proteins transporting substrates that range from ions to sugars, amino acids, biogenic amines, lipids, and both hydrophilic and lipophilic xenobiotics (including anticancer drugs, antimicrobial agents, and drugs of abuse).

It is obviously of intrinsic interest to understand how one or several molecules can be translocated through the hydrophobic core of the lipid bilayer in a way that prevents a short circuit. In addition, it is self-evident that TMTs are vital to afford the selective excretion and retention of solutes in a multicellular organism. It has long been known that TMTs are very important targets of therapeutically relevant drugs. In fact, in the early 1960s, Axelrod, Whitby, and Hertting made the seminal discovery that antidepressant drugs block the transport of monoamines. TMTs for norepinephine, serotonin, and dopamine are still exploited as the most important drug targets for the treatment of depression, narcolepsy, and ADHD. TMTs are not only important as therapeutic targets but are also relevant for understanding the pathophysiology of diseases, the individual variability in susceptibility both to drugs and to environmental input. Subtle differences may, for instance, predispose to diseases (e.g., depression or psychosis) or may confer resistance to pharmacotherapy. Important examples for these nontarget proteins are the product of the MDR1 gene (multidrug resistance protein 1/ABCB1 or P-glycoprotein, P-gp) and other members of the ABC transporter family, including BCRP/ABCG2, MRP1/ABCC1, and MRP2/ABCC2. Bile salts are also transported by an ABC transporter (ABCB11). Thus, it is of clinical relevance to explore the role of canalicular ABC transporters. They modulate the milieu in the downstream bile ducts and thus affect the function of cholangiocytes. They also play a prominent role in bile duct injury.

Previously, “transporters as drug carriers” focused on drug delivery and disposition. In this book, we focus on the transporters as drug targets themselves. Many transporters are well-known drug targets like the monoamine transporters, where compounds have been clinically approved for the treatment of depression disorders, but new transporter targets are also coming up. For the latter transporter group, development of tool compounds is critical to complement information gained by biological means like knockout studies in the validation of these transporters as drug targets. The book is by no means comprehensive, but it will focus on some of the most important well-established transporter drug targets and present some of the new promising transporters along with the wealth of information that has been gained in recent years on the molecular structure from X-ray crystallographic studies. In combination with molecular pharmacological and/or structure–activity relationship studies, this has provided detailed insights into uptake mechanisms, how the compounds interact with transporters and modulate their action.

We would like to thank all authors for their excellent contributions and also for their patience during the editing process. We would also like to express our sincere appreciation to Frank Weinreich, Waltraud Wüst, and the helpful hands at Wiley-VCH for their excellent support in the production of this book. Finally, we also thank Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers for their enthusiasm and continuous efforts to provide the medicinal chemistry community with this outstanding Methods and Principles series of books.

Enjoy reading!
July 2016:
Gerhard F. Ecker, Vienna
Rasmus P. Clausen, Copenhagen
Harald H. Sitte, Vienna