Details

Protein-Protein Interactions in Drug Discovery


Protein-Protein Interactions in Drug Discovery


Methods and Principles in Medicinal Chemistry, Band 56 2. Aufl.

von: Alexander Dömling, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

147,99 €

Verlag: Wiley-VCH
Format: EPUB
Veröffentl.: 02.01.2013
ISBN/EAN: 9783527648221
Sprache: englisch
Anzahl Seiten: 334

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Beschreibungen

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. <br> 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.<br> <br> From the contents:<br> <br> * Prediction of intra- and inter-species protein-protein interactions facilitating systems biology studies<br> * Modulators of protein-protein interactions: The importance of Three-Dimensionality<br> * Interactive technologies for leveraging the known chemistry of anchor residues <br> * SH3 Domains as Drug Targets<br> * P53 MDM2 Antagonists: Towards Non Genotoxic Anticancer Treatments<br> * Inhibition of LFA-1/ICAM interaction for treatment of autoimmune diseases<br> * The PIF-binding pocket of AGC kinases<br> * Peptidic inhibitors of protein-protein interactions for cell adhesion receptors<br> * The REPLACE Strategy for generating Non-ATP competitive Inhibitors of Cell-Cycle Protein Kinases<br> <br> and more<br>
Preface<br> <br> PROTEIN-PROTEIN INTERACTIONS: AN OVERVIEW<br> Introduction<br> Role of PPIs in Human Physiology<br> Regulation of PPIs<br> Structural Features of PPI Interfaces<br> Identification of PPI Inhibitors<br> Conclusions and Outlook<br> <br> PREDICTION OF INTRA- AND INTERSPECIES PROTEIN-PROTEIN INTERACTIONS FACILITATING SYSTEMS BIOLOGY STUDIES<br> Introduction: Relevance of Interactome Studies to Disease and Drug Discovery<br> Our Current Knowledge of Interactomes Identified from Experiments is Incomplete<br> Reliability of Interactions Identified Experimentally<br> Computational Methods for PPI Prediction<br> Sources of Biological Data in Use to Predict PPIs<br> Survey of Current Interactomes<br> <br> MODULATORS OF PROTEIN-PROTEIN INTERACTIONS: IMPORTANCE OF THREE-DIMENSIONALITY<br> Introduction<br> Study<br> Discussion<br> Summary<br> <br> A LEAP INTO THE CHEMICAL SPACE OF PROTEIN-PROTEIN INTERACTION INHIBITORS<br> Introduction<br> Types of Interaction<br> Properties of the Interface<br> Orthosteric versus Allosteric Modulation<br> Leap into the iPPI Chemical Space<br> Case Study<br> Conclusions<br> <br> INTERACTIVE TECHNOLOGIES FOR LEVERAGING THE KNOWN CHEMISTRY OF ANCHOR RESIDUES TO DISRUPT PROTEIN INTERACTIONS<br> Introduction<br> Druggable Sites in PPIs<br> Structure-Based Library Design -<br> A Powerful Alternative to High-Throughput Screening<br> New MCR Chemistry to Design PPI Antagonists<br> Virtual Screening<br> New Interactive Modeling Techniques for Medicinal Chemists<br> New Ideas: Hit Rate Validation of Achor-Centered Screening of p53/MDM2/4<br> Summary<br> <br> SH3 DOMAINS AS DRUG TARGETS<br> Introduction<br> Structure<br> Variability<br> SH3 Binding Motifs<br> Selectivity<br> Drug Target Selection<br> Inhibition Strategies: Peptides and Peptoide Inhibitors<br> Small-Molecule Inhibitors<br> Conclusions<br> <br> p53/MDM2 ANTAGONISTS: TOWARDS NONGENOTOXIC ANTICANCER TREATMENTS<br> Introduction<br> p53/MDM2 PPI is Characterized by Many Cocrystal Structures<br> Nutlins: First-In-Class MDM2 Antagonists<br> Johnson & Johnson: Benzodiazepines<br> Amgen: Chromenotriazolopyrimidines & Piperidones<br> University of Michigan: Spirooxindole<br> University of Pittsburgh: Ugi Based Compounds<br> University of Newcastle: Some Scaffolds With No Structural Biology Information<br> Outlook<br> <br> INHIBITION OF LFA-1K/ICAM INTERACTION FOR THE TREATMENT OF AUTOIMMUNE DISEASES<br> Introduction<br> Integrin Structure and Activation<br> Direct Inhibition of the LFA-1/ICAM Interaction<br> Allosteric Inhibitors of the LFA-1/ICAM Interaction -<br> IDAS Site<br> Summary<br> <br> THE PIF POCKET OF AGC KINASES: A TARGET SITE FOR ALLOSTERIC MODULATORS AND PROTEIN-PROTEIN INTERACTION INHIBITORS<br> Introduction<br> Discovery and Physiological Functions of the PIF Pocket<br> Properties of the PIF Pocket Relevant to Drug Development<br> Small-Molecule PIF Pocket Ligands<br> Potential Supportive Effects Enhancing the Cellular Activity of PIF Pocket-Binding Modulators<br> Conclusions<br> <br> RETOSIBAN AND EPELSIBAN: POTENT AND SELECTIVE ORALLY AVAILABLE OXYTOCIN ANTAGONISTS<br> Introduction<br> Aryl-2,5-DKP Template Discovery and Initial Structure-Activity Relationship Studies<br> Synthesis of the RRR and RRS 6-Indanyl-3-isobutyl-7-aryl-2,5-DKP Secondary Amides<br> Comparison of Crystal Structures of Oxytocin and 2,5-DKPs<br> Pharmacokinetics and Property-Based Design<br> In Vivo Potency of 2',4'-Diflurophenyl Dimethylamide 22<br> Synthesis of Tertiary Amides<br> Summary of Lead Oxytocin Antagonist 2',4'-Diflurophenyl Dimethylamide 22<br> Further Modifications, Five- and Six-Membered Heterocyclic Derivatives<br> Five-Membered Heterocyclic Derivatives and Retosiban<br> Summary of Lead Oxytocin Antagonist Retosiban 56<br> Six-Membered Heterocyclic Derivatives and Epelsiban<br> Summary of Lead Oxytocin Antagonist Epelsiban 77<br> Comparison of Lead Compounds<br> Conclusions<br> <br> PEPTIDIC INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS FOR CELL ADHESION RECEPTORS: RGD PEPTIDES AND BEYOND<br> Introduction<br> From the Discovery of the RGD Motif in FN to the First Selective Cyclic RGD Peptide<br> N-Methylation of c(RGDfV): Cilengitide and Beyond<br> isoDGR Sequence as a New Integrin-Binding Motif<br> Conclusions<br> <br> REPLACE STRATEGY FOR GENERATING NON-ATP-COMPETITIVE INHIBITORS OF CELL CYCLE PROTEIN KINASES<br> Introduction<br> Inhibition of CDKs Through the Cyclin Groove<br> Inhibitors of PLKs<br> Conclusions<br> <br> Index<br>
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.<br>
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. <p>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.</p>

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