Transporters As Drug Targets

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.

Gerhard Ecker is Full Professor for Pharmacoinformatics at the Department of Pharmaceutical Chemistry, University of Vienna (Austria). His main scientific interests are pharmacoinformatic approaches to target drug transporters, in silico screening methods for promiscuous targets and antitargets, and new approaches for data integration and data mining.

Rasmus Pr?torius Clausen is Associate Professor at Dept. Drug Design and Pharmacology, University of Copenhagen (former Royal School of Pharmacy) where he also did post-doctoral studies with P. Krogsgaard-Larsen. His main research topics are neuromedicinal chemistry with focus on glutamate, GABA and GHB, and epigenetic medicinal chemistry. He has a M.Sc. degree from University of Southern Denmark (Chemistry/Cell Biology) and a PhD degree from the University of Aarhus (Denmark).

Harald Sitte studied Medicine at the Universities of Innsbruck and Vienna (Austria). He was appointed Professor for Psychopharmacology at Vienna Medical University in 2010. His main scientific research interests are the structure-function relationships in neurotransmitter transporters and the pharmacological activity of psychopharmacological medicines and drugs of abuse.

Preface XIII

A Personal Foreword XVII

1 Insights into Transporter Classifications: an Outline of Transporters as Drug Targets 1
Michael Viereck, Anna Gaulton, and Daniela Digles

1.1 Introduction 1

1.2 Available Transporter Classifications 2

1.3 Function versus Sequence Similarity 7

1.4 Merged Top-Level Transporter Classification 7

1.5 Choice and Design of the New ChEMBL Classification 11

1.6 Transporter as Drug Targets 12

1.7 Drug Targets in the SLC Classification 15

1.8 Conclusions 17

Acknowledgment 17

References 18

2 New Trends in Antidepressant Drug Research 21
Benny Bang-Andersen, Klaus P. Bøgesø, Jan Kehler, and Connie Sánchez

2.1 Introduction 21

2.2 Reuptake Blockers 26

2.3 Multimodal Drugs 36

2.4 Conclusions 42

List of Abbreviations 42

References 43

3 The Molecular Basis of the Interaction Between Drugs and Neurotransmitter Transporters 53
Harald H. Sitte, Thomas Stockner, and Michael Freissmuth

3.1 Introduction 53

3.2 Crystal Structures of SLC6 Transporters 55

3.3 The Binding Site Proper 60

3.4 The Transport Cycle 61

3.5 Conclusions and Perspectives 63

Acknowledgments 64

References 64

4 γ-Aminobutyric Acid and Glycine Neurotransmitter Transporters 69
Petrine Wellendorph, Julie Jacobsen, Jonas Skovgaard-Petersen, Andreas Jurik, Stine B. Vogensen, Gerhard Ecker, Arne Schousboe, Povl Krogsgaard-Larsen, and Rasmus P. Clausen

4.1 Introduction 69

4.2 GABA Transporters 73

4.3 Glycine Transporters 90

4.4 Conclusions and Future Perspectives 95

References 96

5 ABC Transporters: From Targets to Antitargets and Back 107
Gerhard F. Ecker

5.1 Introduction 107

5.2 ABC Transporter as Drug Targets 109

5.3 ABC Transporter: from Targets to Antitargets 111

5.4 Pharmacochaperones and Beyond 113

5.5 Conclusions and Outlook 114

Acknowledgment 115

References 115

6 ABC Transporters Involved in Cholestasis 119
Frans J. C. Cuperus, Julien Gautherot, Emina Halilbasic, Thierry Claudel, and Michael Trauner

6.1 Introduction 119

6.2 Canalicular ABC Transporters 122

6.3 Basolateral ABC Transporters 136

6.4 Nuclear Receptors as Drug Targets 140

6.5 Ursodeoxycholic Acid Treatment in Cholestatic Liver Disease 144

6.6 Conclusions 145

References 145

7 Recent Advances in Structural Modeling of ABC Transporters 167
Dennis Haake, Peter Chiba, and Gerhard F. Ecker

7.1 Introduction 167

7.2 ABC Transporter Modeling Attempts Since 2001 168

7.3 Retraction of Five Transporter Structures 170

7.4 First Mammalian ABC Transporter Structure 173

7.5 Conclusions and Perspectives 175

Acknowledgment 175

References 175

8 PET Imaging of ABC Transporters at the Blood–Brain Barrier 179
Oliver Langer

8.1 The Blood–Brain Barrier 179

8.2 The Brain as a Pharmacological Sanctuary 180

8.3 Implication of ABC Transporters in Neurological Disorders 180

8.4 Positron Emission Tomography 181

8.5 PET Imaging of ABC Transporters 181

8.6 Challenges in Designing PET Tracers for ABC Transporters 184

8.7 Potential Applications of PET Tracers for ABC Transporters 184

8.8 Overview of Available PET Tracers for Cerebral ABC Transporters 185

8.9 Summary 191

Abbreviations 191

References 191

9 The Systems Biology of Transporters – Targeting the Regulatory System for Transporters (FXR/RXR) 199
Antimo Gioiello, Maura Marinozzi, Bruno Cerra, Chiara Custodi, Roberto Pellicciari, and Antonio Macchiarulo

9.1 Introduction 199

9.2 Discovery and Pharmacological Characterization of FXR 200

9.3 Regulation of the Hepatobiliary Transport System by FXR 201

9.4 Genetic and Structural Properties of FXR 207

9.5 FXR Ligands 209

9.6 Conclusions and Perspectives 221

References 221

10 ANO1 as a Novel Drug Target 231
Anke Bill and Larry Alex Gaither

10.1 Introduction 231

10.2 ANO1: a Calcium Activated Chloride Channel 232

10.3 Pharmacological Targeting of ANO1 238

10.4 ANO1 as a Therapeutic Target 241

10.5 Concluding Remarks 246

References 247

11 Ligand Discovery for the Nutrient Transporters ASCT2 and LAT-1 from Homology Modeling and Virtual Screening 253
Claire Colas and Avner Schlessinger

11.1 Solute Carriers in Cancer Metabolism 253

11.2 In Silico Methods for Structure-based Drug Design 255

11.3 Emerging Cancer Metabolism Targets 260

11.4 Conclusions and Future Outlook 263

Acknowledgment 265

References 265

12 Organic Anion Transporting Polypeptides as Drug Targets 271
Eleni Kotsampasakou and Gerhard F. Ecker

12.1 Introduction 271

12.2 OATPs and Genetic Diseases 285

12.3 OATPs and Cancer 286

12.4 OATPs as Diagnostic Markers 301

12.5 OATPs and Selective Delivery of Drugs 301

12.6 Potential Protective Role of OATPs 309

12.7 OATPs and Drug–Drug Interactions 311

12.8 Conclusions and Outlook 312

Acknowledgments 313

Abbreviation List 313

References 314

Index 325

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Transporters As Drug Targets

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Author Biography

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