Main description:

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 and more

Contents:

List of Contributors XI Preface XV A Personal Foreword XVII 1 Protein Protein 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 Protein Protein 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 Protein Protein 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 Protein Protein Interaction Inhibitors 63 Bruno O. Villoutreix, C. Labbe, 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. Domling 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 Domling 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 Protein Protein 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 Protein Protein 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