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Protein-Protein Interactions in Drug Discovery

Alexander Dömling (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-64822-1
334 pages
January 2013
Protein-Protein Interactions in Drug Discovery (3527648224) cover image


Treating protein-protein interactions as a novel and highly promising class of drug targets, this volume introduces the underlying strategies step by step, from the biology of PPIs to biophysical and computational methods for their investigation.
The main part of the book describes examples of protein targets for which small molecule modulators have been developed, covering such diverse fields as cancer, autoimmune disorders and infectious diseases. Tailor-made for the practicing medicinal chemist, this ready reference includes a wide selection of case studies taken straight from the development pipeline of major pharmaceutical companies to illustrate the power and potential of this approach.

From the contents:

* Prediction of intra- and inter-species protein-protein interactions facilitating systems biology studies
* Modulators of protein-protein interactions: The importance of Three-Dimensionality
* Interactive technologies for leveraging the known chemistry of anchor residues
* SH3 Domains as Drug Targets
* P53 MDM2 Antagonists: Towards Non Genotoxic Anticancer Treatments
* Inhibition of LFA-1/ICAM interaction for treatment of autoimmune diseases
* The PIF-binding pocket of AGC kinases
* Peptidic inhibitors of protein-protein interactions for cell adhesion receptors
* The REPLACE Strategy for generating Non-ATP competitive Inhibitors of Cell-Cycle Protein Kinases

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Table of Contents

List of Contributors XI

Preface XV

A Personal Foreword XVII

1 ProteinProtein Interactions: An Overview 1
Christian Ottmann

1.1 Introduction 1

1.2 Role of PPIs in Human Physiology 2

1.3 Regulation of PPIs 3

1.4 Structural Features of PPI Interfaces 3

1.5 Identification of PPI Inhibitors 10

1.6 Conclusions and Outlook 13

References 14

2 Prediction of Intra- and Interspecies ProteinProtein Interactions Facilitating Systems Biology Studies 21
Sylvia Schleker, Seshan Ananthasubramanian, Judith Klein-Seetharaman, and Madhavi K. Ganapathiraju

2.1 Introduction: Relevance of Interactome Studies to Disease and Drug Discovery 21

2.2 Our Current Knowledge of Interactomes Identified from Experiments is Incomplete 23

2.3 Reliability of Interactions Identified Experimentally 24

2.4 Computational Methods for PPI Prediction 27

2.5 Sources of Biological Data in Use to Predict PPIs 30

2.6 Survey of Current Interactomes 32

References 43

3 Modulators of ProteinProtein Interactions: Importance of Three-Dimensionality 55
David C. Fry and Sung-Sau So

3.1 Introduction 55

3.2 Study 56

3.3 Discussion 58

3.4 Summary 61

References 61

4 A Leap into the Chemical Space of ProteinProtein Interaction Inhibitors 63
Bruno O. Villoutreix, C. Labbé, David Lagorce, Guillaume Laconde, and Olivier Sperandio

4.1 Introduction 63

4.2 Types of Interaction 64

4.3 Properties of the Interface 65

4.4 Orthosteric versus Allosteric Modulation 66

4.5 Leap into the iPPI Chemical Space 66

4.6 Case Study 68

4.7 Conclusions 80

References 81

5 Interactive Technologies for Leveraging the Known Chemistry of Anchor Residues to Disrupt Protein Interactions 85
Carlos J. Camacho, David R. Koes, and Alexander S. Dömling

5.1 Introduction 85

5.2 Druggable Sites in PPIs 86

5.3 Structure-Based Library Design – A Powerful Alternative to High-Throughput Screening 87

5.4 New MCR Chemistry to Design PPI Antagonists 89

5.5 Virtual Screening 90

5.6 New Interactive Modeling Techniques for Medicinal Chemists 93

5.7 New Ideas: Hit Rate Validation of Anchor-Centered Screening of p53/MDM2/4 95

5.8 Summary 96

References 97

6 SH3 Domains as Drug Targets 101
James Luccarelli, Sam Thompson, and Andrew D. Hamilton

6.1 Introduction 101

6.2 Structure 101

6.3 Variability 102

6.4 SH3 Binding Motifs 104

6.5 Selectivity 111

6.6 Drug Target Selection 114

6.7 Inhibition Strategies: Peptide and Peptoid Inhibitors 114

6.8 Small-Molecule Inhibitors 119

6.9 Conclusions 122

References 122

7 p53/MDM2 Antagonists: Towards Nongenotoxic Anticancer Treatments 129

Kareem Khoury, Tad A. Holak, and Alexander Dömling

7.1 Introduction 129

7.2 p53/MDM2 PPI is Characterized by Many Cocrystal Structures 130

7.3 Nutlins: First-In-Class MDM2 Antagonists 131

7.4 Johnson & Johnson: Benzodiazepines 133

7.5 Amgen: Chromenotriazolopyrimidines & Piperidones 137

7.6 University of Michigan: Spirooxindole 148

7.7 University of Pittsburgh: Ugi Based Compounds 153

7.8 University of Newcastle: Some Scaffolds With No Structural Biology Information 155

7.9 Outlook 161

References 161

8 Inhibition of LFA-1/ICAM Interaction for the Treatment of Autoimmune Diseases 165

Kevin M. Guckian and Daniel M. Scott

8.1 Introduction 165

8.2 Integrin Structure and Activation 166

8.3 Direct Inhibition of the LFA-1/ICAM Interaction 168

8.4 Allosteric Inhibitors of the LFA-1/ICAM interaction – IDAS Site 171

8.5 Summary 183

References 183

9 The PIF Pocket of AGC Kinases: A Target Site for Allosteric Modulators and ProteinProtein Interaction Inhibitors 187
Matthias Engel

9.1 Introduction 187

9.2 Discovery and Physiological Functions of the PIF Pocket 190

9.3 Properties of the PIF Pocket Relevant to Drug Development 192

9.4 Small-Molecule PIF Pocket Ligands 199

9.4.3 Current State of Research on PIF Pocket-Directed PDK1

9.5 Potential Supportive Effects Enhancing the Cellular Activity of PIF Pocket-Binding Modulators 209

9.6 Conclusions 212

References 215

10 Retosiban and Epelsiban: Potent and Selective Orally Available Oxytocin Antagonists 225
Alan D. Borthwick and John Liddle

10.1 Introduction 225

10.2 Aryl-2,5-DKP Template Discovery and Initial Structure–Activity Relationship Studies 227

10.3 Synthesis of the RRR and RRS 6-Indanyl-3-isobutyl-7-aryl-2,5-DKP Secondary Amides 231

10.4 Comparison of Crystal Structures of Oxytocin and 2,5-DKPs 231

10.5 Pharmacokinetics and Property-Based Design 232

10.6 In Vivo Potency of 2’,4’-Diflurophenyl Dimethylamide 22 235

10.7 Synthesis of Tertiary Amides 236

10.8 Summary of Lead Oxytocin Antagonist 2’,4’-Diflurophenyl Dimethylamide 22 238

10.9 Further Modifications, Five- and Six-Membered Heterocyclic Derivatives 238

10.10 Five-Membered Heterocyclic Derivatives and Retosiban 239

10.11 Summary of Lead Oxytocin Antagonist Retosiban 56 244

10.12 Six-Membered Heterocyclic Derivatives and Epelsiban 244

10.13 Summary of Lead Oxytocin Antagonist Epelsiban 77 252

10.14 Comparison of Lead Compounds 252

10.15 Conclusions 254

References 254

11 Peptidic Inhibitors of ProteinProtein Interactions for Cell Adhesion Receptors: RGD Peptides and Beyond 257
Carlos Mas-Moruno and Horst Kessler

11.1 Introduction 257

11.2 From the Discovery of the RGD Motif in FN to the First Selective Cyclic RGD Peptide 258

11.3 N-Methylation of c(RGDfV): Cilengitide and Beyond 267

11.4 isoDGR Sequence as a New Integrin-Binding Motif 274

11.5 Conclusions 281

References 282

12 REPLACE Strategy for Generating Non-ATP-Competitive Inhibitors of Cell Cycle Protein Kinases 291
Campbell McInnes

12.1 Introduction 291

12.2 Inhibition of CDKs Through the Cyclin Groove 291

12.3 Inhibitors of PLKs 298

12.4 Conclusions 301

References 302

Index 305

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Author Information

Alexander Domling studied Chemistry and Biology at the Technical University Munich, Germany. After obtaining his PhD under the supervision of Ivar Ugi, he spent a postdoctoral year at the Scripps Research Institute in La Jolla (USA) in the group of Nobel Laureate Barry Sharpless. In 2004 he performed his habilitation at the Technical University of Munich. Since 2006 he teaches and performs research at the University of Pittsburgh in the Department of Pharmacy with secondary appointments in Chemistry and Computational Biology. In 2010 he became full professor receiving his tenure in Pittsburgh. Since 2011 he is chairing the department of Drug Design at the University of Groningen/The Netherlands. Dr. Domling is founder of several biotech companies, including Morphochem and Carmolex. His research centers around the discovery of antagonists of protein-protein interactions and other biologically active compounds in the therapeutic areas of oncology, infectious and neglected tropical diseases using ?out-of-the-box? software tools and multicomponent reaction chemistries.
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