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.