High Throughput Screening: The Discovery of Bioactive Substances: Devlin, John P.: 9780824700676: Book: Health & Fitness: eCampus.com

Preface

iii

(14)

Contributors

xvii

I. Natural Products as a Discovery Resource

(144)

John P. Devlin

1. Chemical Diversity and Genetic Equity: Synthetic and Naturally Derived Compounds

(46)

John P. Devlin

I. Introduction

II. Finding lead molecules: diversity is the key

III. Commercial compound purchases

IV. Natural products

V. International relationships

VI. Indigenous knowledge: rich resource or curiosity?

VII. Conclusions

Appendix 1. Test Substance Sources

Appendix 2. Convention on Biological Diversity (1992)

Appendix 3. Clinton Administration's Proposed Interpretation - 1994

Appendix 4. Internet Access to Natural Product Information

2. Microcollection of Plants for Biochemical Profiling

(28)

John P. Devlin

I. Introduction

II. Botanical and chemical diversity

III. Collection scope

IV. Voucher sampling, storage and retrieval

V. Microcollection techniques

VI. Data management and sample preparation

VII. Extraction processes

VIII. Removal of interfering substances

IX. Test sample preparations in microplate format

X. Follow-up and recollection

XI. Chemotaxonomy and phytochemical tracking

XII. Conclusions

3. Enzymes and Microbes as a Source of Chemical Diversity

(22)

Saul L. Neidleman

I. Introduction

II. Production of chemicals by microbial fermentation

III. Production of chemicals by immobilized microorganisms

IV. Foreign protein synthesis by microorganisms

V. Steroid transformations by microorganisms

VI. Effects of substrate composition and environment

VII. The future

4. The Marine Environment as a Discovery Resource

(48)

Gregg R. Dietzman

I. Introduction

II. Scope and diversity

III. Access to marine natural products libraries

IV. Economic concerns

V. Requirements of an effective acquisition program

VI. Ecological concerns

VII. Scale-up development alternatives

VIII. Conclusions

II. Compound Sourcing: Chemically Generated Screening Libraries

147

(128)

Michael R. Pavia

5. Introduction

147

(8)

Michael R. Pavia

I. Overview

II. Solid phase organic chemistry

III. Mixture synthesis and screening

IV. Parallel synthesis of individual compounds

V. Automation

VI. Conclusion

6. Rapidly Expanding Molecular Diversity: Libraries from Libraries

155

(12)

John S. Kiely

Barbara Dorner

John M. Ostresh

Colette Dooley

Richard A. Houghten

I. Introduction

II. Library preparation

III. Deconvolution methods for nonsupport-bound combinatorial libraries

IV. Soluble combinatorial libraries

V. Conclusion

7. Synthesis of Encoded Small Molecule Combinatorial Libraries via ECLiPS

167

(24)

Jack J. Baldwin

Ian Henderson

I. Combinatorial techniques

II. ECLiPS technology

III. Encoded small molecule combinatorial libraries

IV. Conclusion

8. Parallel Organic Synthesis Using Parke-Davis' Diversomer(R) Method

191

(18)

Sheila Hobbs DeWitt

Anthony W. Czarnik

I. Introduction

II. Organic synthesis on solid-support

III. The diversomer apparatus

IV. Robotic interfacing

V. Examples of diversomer syntheses

VI. Information management

VII. Summary and conclusions

9. Rapid Discovery and Optimization of Biologically Active Small Molecules Using Automated Synthesis Methods

209

(14)

Adnan M. M. Mjalli

Barry E. Toyonaga

I. Introduction

II. Ontogen technology

III. Ontogen compound libraries

IV. Conclusion

10. CMT: A Solution Phase Combinatorial Chemistry Approach: Synthesis and Yield Prediction of Phenazines

223

(20)

Ferenc Darvas

Laszlo Kovacs

I. Introduction

II. CMT: Concept and philosophy

III. Experimental

IV. Discussion

11. Design of a Diverse Screening Library

243

(8)

David E. Patterson

Allan M. Ferguson

Richard D. Cramer

Cheryl D. Garr

Ted L. Underiner

John R. Peterson

I. Introduction

II. Matrix chemistry

III. Diversity objectives

IV. Design parameters

V. Example of designed diversity

VI. Summary

12. Automating Combinatorial Chemistry: Challenges and Pitfalls

251

(12)

Jill H. Hardin

Frank R. Smietana

I. Introduction

13. Combi-chem High Throughput Screening for Leads Optimization

263

(12)

Richard M. Kris

Patti Willson

Serene Josiah

Marianne Wildgoose

Helen Yeoman

Viktor Krchnak

Stephen Baum

Stephen Felder

I. Introduction

II. Sample screening results

III. Conclusions

IV. Summary

III. Assay Technologies and Detection Methods

275

(182)

Alfred J. Kolb

14. Introduction

275

(4)

Alfred J. Kolb

I. Using more efficient assay methods to reduce compromises in screening

II. The diversity of HTS methods

III. The future of HTS

15. Bioassay Design and Implementation

279

(28)

Robert W. Wallace

Mark E. Goldman

I. Introduction

II. Target selection

III. Types and characteristics of screening assays

IV. Decision making

16. Scintillation Proximity Assays

307

(10)

Martino Picardo

Kelvin T. Hughes

I. Introduction

II. Automatability of SPA screening assays

III. Assay throughput using SPA

IV. Number of "hits" in SPA HTS assays

V. Assay interference/quench correction

VI. Signal to noise ratios utilized in SPA HTS assays

VII. Total number of data points generated in SPA HTS assays

VIII. Types of compound libraries tested with SPA

IX. SPA and waste disposal

X. Types of scintillation counter used

XI. Conclusions

17. FlashPlate(TM) Technology

317

(12)

Beverly A. Brown

Margaret Cain

Jeff Broadbent

Sharon Tompkins

Georgette Henrich

Rich Joseph

Sally Casto

Harry Harney

Rick Greene

Ron Delmondo

Simon Ng

I. Principles and characteristics of FlashPlate scintillation counting

II. Receptor binding assays on FlashPlate

III. Live cell assays on FlashPlate

IV. Enzyme assays on FlashPlate

V. Radioimmunoassays on FlashPlate

VI. Summary

18. Assays For Small Molecule Agonists and Antagonists of the Neurotrophin Receptors

329

(16)

Maureen H. Beresini

Michael D. Sadick

Amy L. Galloway

Randy Yen

Sherry H. Yeh

Andy C. Chang

David L. Shelton

Wai Lee T. Wong

I. Introduction

II. Receptor binding assay

III. Receptor activation assay

IV. Assay automation

V. Summary

19. A Homogeneous, Time-Resolved Fluorescence Method for Drug Discovery

345

(16)

Alfred J. Kolb

Jocelyn W. Burke

Gerard Mathis

I. Introduction

II. The theory of HTRF(TM)

III. Applications of HTRF

IV. Instrumentation and robotics

V. Conclusion

20. Time-Resolved Fluorometry: Advantages and Potentials

361

(16)

Ilkka Hemmila

I. Introduction

II. Fluorometry

III. Lanthanides as probes

IV. Time-resolved fluorometry in biomedical research

V. Automation

21. Adaptation of Time-Resolved Fluorescence to Homogeneous Screening Formats

377

(12)

Janet M. Kolb

Greg Yamanaka

Susan P. Manly

I. Introduction

II. Materials and methods

III. Results and discussion

IV. Summary of advantages

22. Fluorescence Polarization

389

(12)

J. Richard Sportsman

Sandra K. Lee

Hara Dilley

Robert Bukar

I. Introduction

II. The potential of fluorescence polarization

III. Theory of fluorescence polarization

IV. Instrumentation

V. High Throughput Screening and FP

VI. Assay characteristics

VII. Data analysis

VIII. Challenges in High Throughput Screening by FP

23. Reporter Gene Assay Applications

401

(12)

Winfried Scheirer

I. Introduction

II. Reporter genes and their products

III. Detection techniques and their improvement

IV. Future aspects

24. Development of a Gene Expression-Based Screen Using Quantitative Polymerase Chain Reaction

413

(14)

D. K. H. Lee

E. T. Wilkinson

S. Cheifetz

S. A. De Grandis

I. Introduction

II. "Target" versus "marker" approaches

III. Development of a gene expression-based screen (GEBS)

IV. Throughput of GEBS

25. High-Performance Microphysiometry in Drug Discovery

427

(16)

M. Liisa Alajoki

Gregory T. Baxter

William R. Bemiss

David Blau

Luc J. Bousse

Samuel D. H. Chan

Timothy D. Dawes

Karen M. Hahnenberger

James M. Hamilton

Philip Lam

Richard J. McReynolds

Douglas N. Modlin

John C. Owicki

J. Wallace Parce

Dana Redington

Knute Stevenson

H. Garrett Wada

Jana Williams

I. Introduction

II. Summary of microphysiometry

III. Biological issues

IV. High-performance microphysiometry

V. Future extensions of microphysiometry

VI. Conclusion

26. Bio-analytical Applications of BIAcore, an Optical Biosensor

443

(14)

Francois Legay

Patrick Albientz

Rudiger Ridder

I. Introduction

II. System design

III. Applications

IV. Conclusion

IV. Automation and Robotics

457

(92)

Alfred J. Kolb

27. Introduction

457

(4)

Alfred J. Kolb

I. A realistic view of automation and robotics

II. The future of automation and robotics

28. Management and Service Issues of a Centralized Robotic HTS Core

461

(10)

John Babiak

I. Introduction

II. Senior management perceptions and expectations

III. Balancing new technology development and data production

IV. Coping with the monotony of screening

V. Working with scientist customers

VI. Summary

29. Flexible Use of People and Machines

471

(12)

Mark Beggs

John S. Major

I. Automation in the bioscience laboratory

II. Approaches to automation in HTS

III. The HTS process

IV. Implementing an automation project

V. Future prospects for automation in HTS

30. Bar-Code Technology and a Centralized Database: Key Components in a Radioligand Binding Program

483

(10)

Elizabeth A. Kunysz

Melissa Lukes

Douglas W. Bonhaus

I. Introduction

II. Methods

III. Discussion

IV. Glossary of terms

31. Factors for the Successful Integration of Assays, Equipment, Robotics, and Software

493

(16)

Dejan Bojanic

Wilma W. Keighley

Mike J. Russell

Terry P. Wood

I. Introduction

II. Defining the screening objectives

III. Development of the screening infrastructure

IV. Hardware

V. Computing

VI. Further development of the HTS facility

32. Accelerating the Discovery Process with Automation and Robotics: A Sure Bet or a Risky Venture?

509

(16)

Richard K. Brown

Andree Proulx

I. Introduction

II. Background

III. Critical success factors

IV. Examples

V. Conclusions

33. Perspectives on Scheduling

525

(24)

Alain Donzel

Jorge Carmona

L. Andrew Corkan

I. Introduction

II. Scheduling

III. Communication tools

IV. User interface

V. Conclusion

V. Data Retrieval, Handling and Integration

549

(76)

John P. Devlin

34. Introduction

549

(2)

John P. Devlin

35. Database Systems

551

(32)

Barr E. Bauer

I. Introduction

II. Database Architectures

III. Client-server systems

IV. Performance and design considerations

V. Chemical structure databases

VI. Programming considerations

VII. Final summary points

36. Systems Integration

583

(16)

Chip Allee

I. Introduction

II. HTS Data Management

III. Conclusion

37. Data Management and Tracking for Natural Product Programs

599

(26)

Gregg R. Dietzman

I. Introduction

II. User requirements

III. Implementing an effective system

IV. Conclusions

VI. Laboratory Design and Management

625

(44)

Matthew A. Sills

38. Introduction

625

(2)

Matthew A. Sills

39. Planning and Implementing an HTS Program

627

(26)

Matthew A. Sills

Mark Crawford

I. Introduction

II. Program perspective

III. Program logistics

IV. Assays

V. Samples

VI. Resourcing

VII. Management considerations

40. Establishing an HTS Program in a Start-Up Biotechnology Company

653

(16)

Michael D. Boisclair

James Schultz

Dan Maloney

I. Introduction

II. Planning the screening program

III. Samples for screening

IV. Equipping the HTS laboratory

V. Developing high throughout screens

VI. Reagent supply

VII. Data management

VIII. Lead discovery

Index

669


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