High Throughput Screening for Lead Discovery

John G. Houston Maetyn N. Banks Bristol-Myers Squibb Pharmaceutical Research Institute Wallingford, Connecticut

Burger's Medicinal Chemistry and Drug Discovery Sixth Edition, Volume 2: Drug Development Edited by Donald J. Abraham ISBN 0-471-37028-2 © 2003 John Wiley & Sons, Inc.

Contents

1 Introduction, 38

2 History of Lead Discovery and Screening, 38

3 Lead Discovery Process. 41

3.1 Target Discovery and Validation, 42

3.1.1 Gene Function by Homology to Other Defined Genes, 43

3.1.2 Gene Function by Gene Subtraction, 43

3.1.3 Gene Function by Expression Analysis, 43

3.2 Bioassay Design and Screen Construction, 43

3.2.1 Assay Design, 44

3.2.2 Assay Construction, 45

3.2.3 Homogeneous and Non-Homogeneous Biochemical Assays, 46

3.2.3.1 Homogeneous Radioisotopic Assays, 46

3.2.3.2 Homogeneous Non-Radioisotopic Assays, 47

3.2.4 Cellular Assays, 49

3.2.4.1 Cell Proliferation Assays, 50

3.2.4.2 Reporter Gene Assays, 50

3.2.5 Alternate High-Throughput Screening Techniques, 52

3.2.6 Screen Validation and Reagent Scale Up, 53

3.3 Constructing Compound Decks and Screening for Hits, 54

3.3.1 Following the Competition, 54

3.3.2 Systems-Based or Focused Discovery, 54

3.3.3 High-Throughput Screening, 56

3.4 Hit Identification, Profiling, and Candidate Selection, 59

3.4.1 Analyzing Screening Hits, 59

3.4.2 Profiling Hits, 59

4 Technology Infrastructure in High-Throughput Screening, 62

4.1 Automation in High-ThroughputScreening, 63

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