Label-Free Technologies For Drug Discovery / Edition 1

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Overview

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.

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Editorial Reviews

From the Publisher
"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." (Laboratory Journal, 10 March 2011)
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Product Details

  • ISBN-13: 9780470746837
  • Publisher: Wiley
  • Publication date: 5/3/2011
  • Edition number: 1
  • Pages: 348
  • Product dimensions: 6.10 (w) x 9.30 (h) x 0.90 (d)

Table of Contents

Preface.

List of Contributors.

1 The Revolution of Real-Time, Label-Free Biosensor Applications (Rebecca L. Rich and David G. Myszka).

2 Design and Implementation of Vertically Emitting Distributed Feedback Lasers for Biological Sensing (Meng Lu, Steven S. Choi, Chun Ge, Clark J. Wagner, J. Gary Eden, and Brian T. Cunningham).

2.1 Introduction.

2.2 DFB Laser Biosensor Design.

2.3 Fabrication and Instrumentation.

2.4 Experimental Results.

2.5 Conclusions.

3 SPR Screening of Chemical Microarrays for Fragment Based Discovery (Thomas Neumann and Renate Sekul).

3.1 Introduction.

3.2 Key Features of Fragment Screening.

3.3 SPR Fragment Screening.

3.4 Synthesis of Library Compounds.

3.5 Library Design and Array Content.

3.6 Chemical Microarray Production.

3.7 Surface Plasmon Resonance.

3.8 SPR Imaging.

3.9 Array Visualization and Analysis.

3.10 Follow-up.

3.11 Applications: MMP case study.

3.12 Search for New Binding Modes.

3.13 Selectivity Studies.

3.14 Other Target Classes.

3.15 Conclusions.

4 The CellKey System: A Label-Free Cell-Based Assay Platform for Early Drug Discovery Applications (Ryan P. McGuinness, Debra L. Gallant, Yen-Wen Chen, Trisha A. Tutana, Donna L. Wilson, John M. Proctor, H. Roger Tang).

4.1 Introduction.

4.2 Cellular Impedance Technology.

4.3 Target Identification and Validation.

4.4 Screening and Lead Optimization.

4.5 Conclusion.

5 Dynamic and Label-Free Cell-Based Assays using the xCELLigence System (Yama A. Abassi, Alexander Sieler, Manfred Watzele, Xiaobo Wang and Xiao Xu).

5.1 Introduction.

5.2 The xCELLigence system.

5.3 Principle of Detection.

5.4 Applications.

5.5 Functional Assays for G Protein-Coupled Receptors.

5.6 Conclusion.

6 Selecting the Best HTS Hits to Move Forward: ITC Ligand Binding Characterization Provides Guidance (Ronan O'Brien & Richard Brown).

6.1 Introduction.

6.2 Principles of Isothermal Titration Calorimetry (ITC).

6.3 Applications of ITC in Hit Validation.

6.4 Applications of ITC in Fragment-Based Drug Discovery.

6.5 Applications of ITC in Mechanism of Action Studies.

6.6 Applications of ITC in Lead Optimization.

6.7 ITC as an Enzyme Activity Monitor.

6.8 Conclusion.

7 Incorporating Transmitted Light Modalities into High-Content Analysis Assays (Robert Graves).

7.1 Introduction.

7.2 Transmitted Light (Bright Field) Imaging.

7.3 Image Analysis of Phase Contrast Images.

7.4 Conclusion.

8 Nonradioactive Rubidium Efflux Assay Technology for Screening of Ion Channels (Georg C. Terstappen).

8.1 Introduction.

8.2 Ion Channels as Drug Targets.

8.3 Ion Channel Assays and Screening.

8.4 Nonradioactive Rubidium Efflux Assay Based on Atomic Absorption Spectrometry.

8.5 A Typical Assay Protocol.

8.6 Conclusions.

9 Expanding the Scope of HTMS Methods (Tom G. Holt, Jun Wang, Xun Chen, Bernard K. Choi, Neil S. Geoghagen, Kristian K. Jensen, Maxine Jonas, Qi Luo, William A. LaMarr, Lorraine Malkowitz, Can C. Ozbal, Yusheng Xiong, Claude Dufresne, Ming-Juan Luo).

9.1 Introduction.

9.2 Development of Htms Method for Underivatized Cystathionine in Biological Samples Spanning In Vitro, Cell Culture, and Ex Vivo Assays.

9.3 Development of 2D HTMS Method for Plasma-Bound Small Molecules.

9.4 Conclusion.

10 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 (Vered Bronner, Oded Nahshol and Tsafrir Bravman).

10.1 Introduction.

10.2 Optimized Assay Configuration.

10.3 Selection of the Optimal Capture Agent.

10.4 Kinetic Analysis of 192 Human Anti-Il-12 Supernatants.

10.5 Kinetic Analysis of 243 Human Hemoglobin Supernatants.

10.6 Conclusions.

11 Biophysics/Label-Free Assays in Hit Discovery and Verification (Johannes Ottl).

11.1 Introduction.

11.2 Why biophysics?

11.3 Biophysics/Label-Free Toolbox.

11.4 Which Biophysical Measurement at Which Stage of a Drug Discovery Project Flowchart?

11.5 Conclusion.

11.6 Outlook.

12 Harnessing Optical Label-free on Microtiter Plates for Lead Finding From Binding to Phenotypes (Julio Martin).

12.1 Introduction.

12.2 Value Proposition and Advantages Of Label-Free Methodologies.

12.3 Detection Principle of an Optical Label-Free Resonant Grating Sensor.

12.4 Biological Applications of Optical Label-Free In Lead Discovery.

12.5 Current and Future Challenges.

12.6 Conclusion.

13 Use of Label-Free Detection Technologies in the Hit-to-Lead Process: Surface Optical Detection of Cellular Processes (F. Stuhmeier, J. Bradley, E. Fairman, E. Gbekor, P. Hayter, S. Ramsey).

13.1 Introduction.

13.2 Overview of Label-Free Assay Platforms.

13.3 Surface Optical Detection of Cellular Processes.

13.4 Discussion.

14 Cellular Screening for 7TMs Using Label-Free Detection (Jeffrey C. Jerman, Jason Brown and Magalie Rocheville).

14.1 Introduction.

14.2 Results and Discussion.

14.3 Conclusions and Perspective.

14.4 Materials and Methods.

14.5 Acknowledgements.

15 Novartis Evaluation of the ForteBio Octet RED: A Versatile Instrument for Direct-Binding Experiments (Eric Martin, John Wang, Isabel Zaror, Jiamin Yu, Kelly Yan, Mike Doyle, Paul Feucht, Kevin Shoemaker, Bob Warne, Mike Chin, Blisseth Sy, Lukas Leder, Marco Meyerhofer, Charles Wartchow, Danfeng Yao).

15.1 Introduction.

15.2 Methods.

15.3 Results and Discussion.

15.4 Conclusion.

16 The Pyramid Approach to Fragment-Based Biophysical Screening (Glyn Williams).

16.1 Introduction.

16.2 Summary and Conclusions.

16.3 Acknowledgements.

17 Characterisation of Antibodies Against the Active Conformation of Gαi1 Using the SRU-BIND­® Label-Free Detection System (Melanie Leveridge, Chun-Wa Chung and Trevor Wattam).

17.1 Introduction.

17.2 Materials and Methods.

17.3 Results and Discussion.

17.4 Conclusions.

17.5 Acknowledgements.

18 SPR Based Direct Binding Assays in Drug Discovery (Walter Huber).

18.1 Introduction.

18.2 Screening Using SPR-Based Direct Binding Assay.

18.3 Lead Selection using SPR Based Binding Assay.

18.4 Conclusion.

18.5 Acknowledgements.

19 Kinetic Binding Mechanisms: Their Contribution to an Optimal Therapeutic Index (David C. Swinney).

19.1 Introduction.

19.2 Why are Binding Mechanisms and Kinetics Important to Drug Action?

19.3 How Can Kinetics Contribute to an Optimal Mechanism?

19.4 Binding Kinetics Differentiate Physiological Responses.

19.5 Utilization of Binding Kinetics in Drug Discovery. How to get Maximum Value out of Kinetic Analysis?

19.6 Conclusion.

20 ITC: More Than Just Binding Affinities (Ernesto Freire).

20.1 Introduction.

20.2 Why should We Care About Enthalpy and Entropy?

20.3 Conclusion.

Acknowledgements. 

Index.

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