Label-free Technologies for Drug Discovery

by Cooper, Matthew; Mayr, Lorenz M.

Edition: 1st

ISBN13: 9780470746837

ISBN10: 0470746831

Format: Hardcover

Pub. Date: 2011-03-14

Publisher(s): Wiley

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Summary

Over the past two decades the benefits of label-free biosensor analysis have begun to make an impact in the market, and systems are beginning to be used as mainstream research tools in many drug discovery laboratories.Label-Free Technologies For Drug Discovery summarises the latest and emerging developments in label-free detection systems, their underlying technology principles and end-user case studies that reveal the power and limitations of label-free in all areas of drug discovery.Label-free technologies discussed include SPR, NMR, high-throughput mass spectrometry, resonant waveguide plate-based screening, transmitted-light imaging, isothermal titration calorimetry, optical and impedance cell-based assays and other biophysical methods. The technologies are discussed in relation to their use as screening technologies, high-content technologies, hit finding and hit validation strategies, mode of action and ADME/T, access to difficult target classes, cell-based receptor/ligand interactions particularly orphan receptors, and antibody and small molecule affinity and kinetic analysis.Label-Free Technologies For Drug Discovery is an essential guide to this emerging class of tools for researchers in drug discovery and development, particularly high-throughput screening and compound profiling teams, medicinal chemists, structural biologists, assay developers, ADME/T specialists, and others interested in biomolecular interaction analysis.

Author Biography

Dr Matthew Cooper, Institute for Molecular Bioscience, University of Queensland, Australia
Dr Cooper is a scientist and entrepreneur. He is Co-Founder and Chief Scientific Officer of Akubio Ltd; and Founder and Managing Director of Cambridge Medical Innovations. He has written more than 60 publications and invited reviews in leading scientific journals including Nature Biotechnology, Nature Cell Biology, and Nature Drug Discovery.

Dr Lorenz M. Mayr, Biology Unit, Protease Platform, Novartis Pharma AG, Basel, Switzerland
Dr Mayer is Head of the Biology Unit at the Protease Platform, Centre of Proteomic Chemistry (CPC), at Novartis Pharma AG with responsibility for target finding and target validation, protein expression, assay development and compound screening and profiling for all protease projects. Dr. Mayr is a member of several editorial and scientific advisory boards and also serves as a member at the Board of Directors of SBS, the Society of Biomolecular Sciences.

Preface
List of Contributors
The Revolution of Real-Time, Label-Free Biosensor Applications
Design and Implementation of Vertically Emitting Distributed Feedback Lasers for Biological Sensing
Introduction
DFB Laser Biosensor Design
Fabrication and Instrumentation
Experimental Results
Conclusions
SPR Screening of Chemical Microarrays for Fragment Based Discovery
Introduction
Key Features of Fragment Screening
SPR Fragment Screening
Synthesis of Library Compounds
Library Design and Array Content
Chemical Microarray Production
Surface Plasmon Resonance
SPR Imaging
Array Visualization and Analysis
Follow-up
Applications: MMP case study
Search for New Binding Modes
Selectivity Studies
Other Target Classes
Conclusions
The CellKey System: A Label-Free Cell-Based Assay Platform for Early Drug Discovery Applications
Introduction
Cellular Impedance Technology
Target Identification and Validation
Screening and Lead Optimization
Conclusion
Dynamic and Label-Free Cell-Based Assays using the xCELLigence System
Introduction
The xCELLigence system
Principle of Detection
Applications
Functional Assays for G Protein-Coupled Receptors
Conclusion
Selecting the Best HTS Hits to Move Forward: ITC Ligand Binding Characterization Provides Guidance
Introduction
Principles of Isothermal Titration Calorimetry (ITC)
Applications of ITC in Hit Validation
Applications of ITC in Fragment-Based Drug Discovery
Applications of ITC in Mechanism of Action Studies
Applications of ITC in Lead Optimization
ITC as an Enzyme Activity Monitor
Conclusion
Incorporating Transmitted Light Modalities into High-Content Analysis Assays
Introduction
Transmitted Light (Bright Field) Imaging
Image Analysis of Phase Contrast Images
Conclusion
Nonradioactive Rubidium Efflux Assay Technology for Screening of Ion Channels
Introduction
Ion Channels as Drug Targets
Ion Channel Assays and Screening
Nonradioactive Rubidium Efflux Assay Based on Atomic Absorption Spectrometry
A Typical Assay Protocol
Conclusions
Expanding the Scope of HTMS Methods
Introduction
Development of Htms Method for Underivatized Cystathionine in Biological Samples Spanning In Vitro, Cell Culture, and Ex Vivo Assays
Development of 2D HTMS Method for Plasma-Bound Small Molecules
Conclusion
A Novel Multiplex SPR Array for Rapid Screening and Affinity Determination of Monoclonal Antibodies: The ProteOn XPR36 Label Free System: Kinetic Screening of Monoclonal Antibodies
Introduction
Optimized Assay Configuration
Selection of the Optimal Capture Agent
Kinetic Analysis of 192 Human Anti-Il-12 Supernatants
Kinetic Analysis of 243 Human Hemoglobin Supernatants
Conclusions
Biophysics/Label-Free Assays in Hit Discovery and Verification
Introduction
Why biophysics?
Biophysics/Label-Free Toolbox
Which Biophysical Measurement at Which Stage of a Drug Discovery Project Flowchart?
Conclusion
Outlook
Harnessing Optical Label-free on Microtiter Plates for Lead Finding From Binding to Phenotypes
Introduction
Value Proposition and Advantages Of Label-Free Methodologies
Detection Principle of an Optical Label-Free Resonant Grating Sensor
Biological Applications of Optical Label-Free In Lead Discovery
Current and Future Challenges
Conclusion
Use of Label-Free Detection Technologies in the Hit-to-Lead Process: Surface Optical Detection of Cellular Processes
Introduction
Overview of Label-Free Assay Platforms
Surface Optical Detection of Cellular Processes
Discussion
Cellular Screening for 7TMs Using Label-Free Detection
Introduction
Results and Discussion
Conclusions and Perspective
Materials and Methods
Acknowledgements
Novartis Evaluation of the ForteBio Octet RED: A Versatile Instrument for Direct-Binding Experiments
Introduction
Methods
Results and Discussion
Conclusion
The Pyramid Approach to Fragment-Based Biophysical Screening
Introduction
Summary and Conclusions
Acknowledgements
Characterisation of Antibodies Against the Active Conformation of G_¿_i1 Using the SRU-BIND® Label-Free Detection System
Introduction
Materials and Methods
Results and Discussion
Conclusions
Acknowledgements
SPR Based Direct Binding Assays in Drug Discovery
Introduction
Screening Using SPR-Based Direct Binding Assay
Lead Selection using SPR Based Binding Assay
Conclusion
Acknowledgements
Kinetic Binding Mechanisms: Their Contribution to an Optimal Therapeutic Index
Introduction
Why are Binding Mechanisms and Kinetics Important to Drug Action?
How Can Kinetics Contribute to an Optimal Mechanism?
Binding Kinetics Differentiate Physiological Responses
Utilization of Binding Kinetics in Drug Discovery. How to get Maximum Value out of Kinetic Analysis?
Conclusion
ITC: More Than Just Binding Affinities
Introduction
Why should We Care About Enthalpy and Entropy?
Conclusion
Acknowledgements
Index.
Table of Contents provided by Publisher. All Rights Reserved.