Dömling Protein-Protein Interactions in Drug Discovery

1. Auflage 2013
ISBN: 978-3-527-64823-8
Verlag: Wiley-VCH
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band 56, 314 Seiten, E-Book

Reihe: Methods and Principles in Medicinal Chemistry

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

Autoren/Hrsg.

Dömling, Alexander

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Inhaltsverzeichnis

Preface   PROTEIN-PROTEIN INTERACTIONS: AN OVERVIEW Introduction Role of PPIs in Human Physiology Regulation of PPIs Structural Features of PPI Interfaces Identification of PPI Inhibitors Conclusions and Outlook   PREDICTION OF INTRA- AND INTERSPECIES PROTEIN-PROTEIN INTERACTIONS FACILITATING SYSTEMS BIOLOGY STUDIES Introduction: Relevance of Interactome Studies to Disease and Drug Discovery Our Current Knowledge of Interactomes Identified from Experiments is Incomplete Reliability of Interactions Identified Experimentally Computational Methods for PPI Prediction Sources of Biological Data in Use to Predict PPIs Survey of Current Interactomes   MODULATORS OF PROTEIN-PROTEIN INTERACTIONS: IMPORTANCE OF THREE-DIMENSIONALITY Introduction Study Discussion Summary   A LEAP INTO THE CHEMICAL SPACE OF PROTEIN-PROTEIN INTERACTION INHIBITORS Introduction Types of Interaction Properties of the Interface Orthosteric versus Allosteric Modulation Leap into the iPPI Chemical Space Case Study Conclusions   INTERACTIVE TECHNOLOGIES FOR LEVERAGING THE KNOWN CHEMISTRY OF ANCHOR RESIDUES TO DISRUPT PROTEIN INTERACTIONS Introduction Druggable Sites in PPIs Structure-Based Library Design - A Powerful Alternative to High-Throughput Screening New MCR Chemistry to Design PPI Antagonists Virtual Screening New Interactive Modeling Techniques for Medicinal Chemists New Ideas: Hit Rate Validation of Achor-Centered Screening of p53/MDM2/4 Summary   SH3 DOMAINS AS DRUG TARGETS Introduction Structure Variability SH3 Binding Motifs Selectivity Drug Target Selection Inhibition Strategies: Peptides and Peptoide Inhibitors Small-Molecule Inhibitors Conclusions   p53/MDM2 ANTAGONISTS: TOWARDS NONGENOTOXIC ANTICANCER TREATMENTS Introduction p53/MDM2 PPI is Characterized by Many Cocrystal Structures Nutlins: First-In-Class MDM2 Antagonists Johnson & Johnson: Benzodiazepines Amgen: Chromenotriazolopyrimidines & Piperidones University of Michigan: Spirooxindole University of Pittsburgh: Ugi Based Compounds University of Newcastle: Some Scaffolds With No Structural Biology Information Outlook   INHIBITION OF LFA-1K/ICAM INTERACTION FOR THE TREATMENT OF AUTOIMMUNE DISEASES Introduction Integrin Structure and Activation Direct Inhibition of the LFA-1/ICAM Interaction Allosteric Inhibitors of the LFA-1/ICAM Interaction - IDAS Site Summary   THE PIF POCKET OF AGC KINASES: A TARGET SITE FOR ALLOSTERIC MODULATORS AND PROTEIN-PROTEIN INTERACTION INHIBITORS Introduction Discovery and Physiological Functions of the PIF Pocket Properties of the PIF Pocket Relevant to Drug Development Small-Molecule PIF Pocket Ligands Potential Supportive Effects Enhancing the Cellular Activity of PIF Pocket-Binding Modulators Conclusions   RETOSIBAN AND EPELSIBAN: POTENT AND SELECTIVE ORALLY AVAILABLE OXYTOCIN ANTAGONISTS Introduction Aryl-2,5-DKP Template Discovery and Initial Structure-Activity Relationship Studies Synthesis of the RRR and RRS 6-Indanyl-3-isobutyl-7-aryl-2,5-DKP Secondary Amides Comparison of Crystal Structures of Oxytocin and 2,5-DKPs Pharmacokinetics and Property-Based Design In Vivo Potency of 2',4'-Diflurophenyl Dimethylamide 22 Synthesis of Tertiary Amides Summary of Lead Oxytocin Antagonist 2',4'-Diflurophenyl Dimethylamide 22 Further Modifications, Five- and Six-Membered Heterocyclic Derivatives Five-Membered Heterocyclic Derivatives and Retosiban Summary of Lead Oxytocin Antagonist Retosiban 56 Six-Membered Heterocyclic Derivatives and Epelsiban Summary of Lead Oxytocin Antagonist Epelsiban 77 Comparison of Lead Compounds Conclusions   PEPTIDIC INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS FOR CELL ADHESION RECEPTORS: RGD PEPTIDES AND BEYOND Introduction From the Discovery of the RGD Motif in FN to the First Selective Cyclic RGD Peptide N-Methylation of c(RGDfV): Cilengitide and Beyond isoDGR Sequence as a New Integrin-Binding Motif Conclusions   REPLACE STRATEGY FOR GENERATING NON-ATP-COMPETITIVE INHIBITORS OF CELL CYCLE PROTEIN KINASES Introduction Inhibition of CDKs Through the

Über Autor(innen)

Alexander Dömling 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. Dömling 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.