High-throughput screening in drug discovery:
Gespeichert in:
| Weitere Verfasser: | |
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| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Weinheim
Wiley-VCH-Verl.
2006
|
| Schriftenreihe: | Methods and principles in medicinal chemistry
35 |
| Schlagworte: | |
| Online-Zugang: | Inhaltstext Inhaltsverzeichnis |
| Beschreibung: | Literaturangaben. Titel fälschlich auf d. Umschlag: High throughput-screening in drug discovery |
| Beschreibung: | XVIII, 343 S. Ill., graph. Darst. 25 cm |
| ISBN: | 9783527312832 3527312838 |
Internformat
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| 246 | 1 | 3 | |a High throughput screening in drug discovery |
| 264 | 1 | |a Weinheim |b Wiley-VCH-Verl. |c 2006 | |
| 300 | |a XVIII, 343 S. |b Ill., graph. Darst. |c 25 cm | ||
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| 490 | 1 | |a Methods and principles in medicinal chemistry |v 35 | |
| 500 | |a Literaturangaben. Titel fälschlich auf d. Umschlag: High throughput-screening in drug discovery | ||
| 650 | 4 | |a Criblage à haut débit (Développement des médicaments) | |
| 650 | 4 | |a Chemistry, Pharmaceutical |x methods | |
| 650 | 4 | |a Drug Design | |
| 650 | 4 | |a Drug Evaluation, Preclinical | |
| 650 | 4 | |a High throughput screening (Drug development) | |
| 650 | 0 | 7 | |a High throughput screening |0 (DE-588)4596131-1 |2 gnd |9 rswk-swf |
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Datensatz im Suchindex
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| adam_text | HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY EDITED BY JOERG HUESER WILEY-
VCH WILEY-VCH VERLAG GMBH & CO. KGAA VII LIST OF CONTENTS PREFACE XIV
LIST OF CONTRIBUTORS XVI PART I CONCEPT OF SCREENING 1 CHEMICAL
GENETICS: USE OF HIGH-THROUGHPUT SCREENING TO IDENTIFY SMALL-MOLECULE
MODULATORS OF PROTEINS INVOLVED IN CELLULAR PATHWAYS WITH THE AIM OF
UNCOVERING PROTEIN FUNCTION SA L CHIANG 1.1 INTRODUCTION 1 1.2 CLASSICAL
AND CHEMICAL GENETICS 1 1.2.1 FORWARD AND REVERSE SCREENS 3 1.3
IDENTIFYING BIOACTIVE MOLECULES 4 1.4 TARGET IDENTIFICATION 5 1.4.1
HYPOTHESIS-DRIVEN TARGET IDENTIFICATION 5 1.4.2 AFFINITY-BASED TARGET
IDENTIFICATION 6 1.4.3 GENOMIC METHODS OF TARGET IDENTIFICATION 7 1.4.4
PROTEOMIC METHODS 9 1.5 DISCOVERY FOR BASIC RESEARCH VERSUS
PHARMACOTHERAPY GOALS 10 1.6 CHEMICAL GENETIC SCREENS IN THE ACADEMIC
SETTING 11 1.7 CONCLUSIONS 12 2 HIGH-THROUGHPUT SCREENING FOR TARGETED
LEAD DISCOVERY JOERG HUESER, EMANUEL LOHRMANN, BERND KALTHOF, NIK
BURKHARDT, ULF BRUEGGEMEIER, AND MARTIN BECHEM 2.1 CHEMICAL LIBRARIES FOR
HIGH-THROUGHPUT SCREENING 15 2.2 PROPERTIES OF LEAD STRUCTURES 17 2.3
CHALLENGES TO HIGH-THROUGHPUT SCREENING 19 2.4 ASSAY TECHNOLOGIES FOR
HIGH-THROUGHPUT SCREENING 21 2.5 LABORATORY AUTOMATION 24 2.6 FROM
TARGET SELECTION TO CONFIRMED HITS - THE HTS WORKFLOW AND ITS VOCABULARY
25 HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY. EDITED BY JOERG HUESER
COPYRIGHT 2006 WILEY-VCH VERLAG GMBH & CO. KGAA, WEINHEIM ISBN:
3-527-31283-8 VIII LIST OF CONTENTS 2.7 SEPARATING SPECIFIC MODULATORS
FROM OFF-TARGET EFFECTS 2.8 DATA ANALYSIS AND SCREENING RESULTS 32 2.9
CONCLUSIONS 34 PART II AUTOMATION TECHNOLOGIES 29 3.1 3.1.1 3.1.2 3.1.3
3.1.4 3.1.5 3.1.6 3.1.7 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.4.1 3.2.4.2
3.2.4.3 3.2.4.4 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3 3.3.1.4 3.3.1.5
3.3.1.6 3.3.1.7 3.3.1.8 3.3.2 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.4 3.4.1
3.4.2 3.4.3 TOOLS AND TECHNOLOGIES THAT FACILITATE AUTOMATED SCREENING
JOHN COMLEY INTRODUCTION - THE NECESSITY TO AUTOMATE 37 COMPOUND
LIBRARIES 37 TARGETS AND DATA POINTS 38 MAIN ISSUES FACING HTS GROUPS
TODAY 38 BENEFITS OF MINIATURIZATION 39 BENEFITS OF AUTOMATED HTS 39
SCREENING STRATEGIES 40 ULTRA HTS (UHTS) 40 SAMPLE CARRIERS 41 A BRIEF
HISTORY OF THE MICROPLATE 41 MICROPLATE USAGE TODAY 41 MICROPLATE ARRAYS
42 NON-MICROPLATE ALTERNATIVES 43 LABCHIPS 43 LABCDS 43 LABBRICK 44
ARRAYED COMPOUND SCREENING 44 LIQUID HANDLING TOOLS 45 MAIN MICROPLATE
DISPENSE MECHANISMS 45 PIN TOOLS 45 AIR AND POSITIVE DISPLACEMENT 45
PERISTALTIC 46 SOLENOID-SYRINGE 4 7 SOLENOID-PRESSURE BOTTLE 47
CAPILLARY SIPPER 48 PIEZOELECTRIC 48 ACOUSTIC TRANSDUCER 48 HTS LIQUID
HANDLING APPLICATIONS AND DISPENSING TECHNOLOGIES USED 49 BULK REAGENT
AND CELL ADDITION 49 COMPOUND REFORMATTING AND NANOLITER DISPENSING 50
CHERRY PICKING AND SERIAL DILUTION 51 MICROPLATE WASHING 52 DETECTION
TECHNOLOGIES 53 MAIN DETECTION MODALITIES USED IN HTS 53 PLATE READERS
54 PLATE IMAGERS 55 LIST OF CONTENTS IX 3.4.3.1 MACRO-IMAGING 56 3.4.3.2
MICRO-IMAGING 57 3.4.4 DISPENSE AND READ DEVICES 60 3.4.5 OTHER
DETECTION TECHNOLOGIES 60 3.4.6 AUTOMATION OF DETECTION TECHNOLOGIES 61
3.4.7 POTENTIAL SOURCES OF READING ERROR 61 3.5 LABORATORY ROBOTICS 62
3.5.1 TRADITIONAL WORKSTATIONS 64 3.5.2 ROBOTIC SAMPLE PROCESSORS 64
3.5.3 PLATE STORAGE DEVICES 64 3.5.4 PLATE MOVING DEVICES 65 3.5.5 FULLY
INTEGRATED ROBOTIC SYSTEMS 65 3.5.6 TURNKEY WORKSTATIONS 66 3.5.7
AUTOMATED CELL CULTURE SYSTEMS 66 3.5.8 COMPOUND MANAGEMENT SYSTEMS 67
3.5.8.1 CURRENT PRACTICE IN COMPOUND MANAGEMENT 67 3.5.8.2 PLATE-BASED
VERSUS TUBE-BASED LIQUID COMPOUND STORAGE 3.5.8.3 ASSOCIATED AUTOMATED
INSTRUMENTATION 70 3.5.8.4 SAMPLE INTEGRITY AND QC TESTING 70 PART III
ASSAY TECHNOLOGIES FUNCTIONAL CELL-BASED ASSAYS FOR TARGETED LEAD
DISCOVERY IN HIGH-THROUGHPUT SCREENING JOERG HUESER, BERND KALTHOF, AND
JOCHEN STRAYLE INTRODUCTION 75 REPORTER GENE TECHNOLOGIES 78 MEMBRANE
POTENTIAL INDICATORS 82 CA 2+ INDICATORS 88 CONCLUSIONS 90 68 4.1 4.2
4.3 4.4 4.5 5.1 5.2 5.2.1 5.2.2 5.2.3 5.3 5.3.1 5.3.2 5.4 5.4.1
BIOCHEMICAL ASSAYS FOR HIGH-THROUGHPUT SCREENING WILLIAM D. MALLENDER,
MICHAEL BEMBENEK, LAWRENCE R. DICK, MICHAEL KURANDA, PING LI, SAURABH
MENON, ENEIDA PARDO AND TOM PARSONS GENERAL CONSIDERATIONS FOR
BIOCHEMICAL HIGH-THROUGHPUT SCREENING 93 EXPRESSION AND PURIFICATION OF
RECOMBINANT ENZYMES 95 DESIGN OF EXPRESSION CONSTRUCTS 98 EXPRESSION
ASSESSMENT AND OPTIMIZATION 99 PURIFICATION 99 PEPTIDASES 102
APPLICATION OF FLUOROGENIC SUBSTRATES TO CONFIGURE PEPTIDASE SCREENS 102
THE VALUE OF CONTINUOUS ASSAYS 107 OXIDOREDUCTASES 107 NAD(P)-DEPENDENT
OXIDOREDUCTASES 108 X LIST OF CONTENTS 5.4.2 NON-NAD(P)
COFACTOR-DEPENDENT OXIDOREDUCTASES 110 5.4.3 OXIDASES OR
OXYGEN-UTILIZING OXIDOREDUCTASES 111 5.4.4 GENERAL CONSIDERATIONS 113
5.5 TRANSFERASES, SYNTHETASES AND LIPID-MODIFYING ENZYMES 114 5.5.1
STREPTAVIDIN-BIOTIN CAPTURE 114 5.5.2 IONIC CAPTURE 117 5.5.3
HYDROPHOBIC CAPTURE 117 5.6 KINASES 120 5.6.1 STREPTAVIDIN-BIOTIN
CAPTURE 120 5.6.2 HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) 122
5.6.3 PYRUVATE KINASE-LACTATE DEHYDROGENASE ASSAY SYSTEM 122 5.7
PITFALLS AND REASONS FOR ASSAY DEVELOPMENT FAILURES 125 6 IMAGE-BASED
HIGH-CONTENT SCREENING - A VIEW FROM BASIC SCIENCES PETER LIPP AND LARS
KAESTNER 6.1 INTRODUCTION 129 6.2 HCS SYSTEMS EMPLOYING CONFOCAL OPTICAL
TECHNOLOGIES 132 6.3 SINGLE-POINT SCANNING TECHNOLOGY 134 6.4 LINE
SCANNING TECHNOLOGY 136 6.5 MULTI-BEAM TECHNOLOGY 138 6.6 STRUCTURED
ILLUMINATION 145 6.7 SUMMARY AND PERSPECTIVES 147 PART IV DATA ANALYSIS
7 METHODS FOR STATISTICAL ANALYSIS, QUALITY ASSURANCE AND MANAGEMENT OF
PRIMARY HIGH-THROUGHPUT SCREENING DATA HANSPETER CUBLER 7.1 INTRODUCTION
151 7.1.1 OVERVIEW 151 7.1.2 PROBLEMS DURING THE ANALYSIS OF PRIMARY HTS
DATA 151 7.2 STATISTICAL CONSIDERATIONS IN ASSAY DEVELOPMENT 155 7.3
DATA ACQUISITION, DATA PREPROCESSING, AND HTS DATA ANALYSIS ENVIRONMENT
158 7.4 DATA NORMALIZATION 160 7.5 ROBUST STATISTICS IN HTS DATA
ANALYSIS 163 7.5.1 THE GENERAL PROBLEM 163 7.5.2 THRESHOLD SETTING - A
SIMPLE MODEL 164 7.5.3 THRESHOLD SETTING - A COMPLEX MODEL 165 7.5.4 THE
MOST IMPORTANT ROBUST ESTIMATION METHODS FOR DATA SUMMARIES 1 65 7.5.5
AN ILLUSTRATIVE EXAMPLE: PERFORMANCE OF LOCATION AND SCALE ESTIMATORS ON
TYPICAL HTS DATA ACTIVITY DISTRIBUTIONS 167 7.5.6 A ROBUST OUTLIER
DETECTION METHOD 168 7.5.7 OUTLIER-RESISTANT VERSIONS OF SIMPLE HTS DATA
QUALITY INDICATORS 170 LIST OF CONTENTS XI 7.6 MEASURES OF HTS DATA
QUALITY, SIGNALING OF POSSIBLE QC PROBLEMS, VISUALIZATIONS 170 7.6.1
TRENDS AND CHANGE POINTS 171 7.6.2 POSITIONAL EFFECTS - SUMMARY
STATISTICS AND VIEWS 175 7.6.3 POSITIONAL EFFECTS - HEAT MAPS, TRELLIS
PLOTS, AND ASSAY MAPS 177 7.6.4 DISTRIBUTION DENSITIES - HISTOGRAMS,
SMOOTHED DISTRIBUTIONS 180 7.6.5 NUMERICAL DIAGNOSTICS AND FULLY
AUTOMATED QC ASSESSMENT 181 7.6.6 POSSIBLE SOURCES OF SYSTEMATIC ERRORS
AND TRENDS 182 7.7 CORRECTION OF POSITION-DEPENDENT RESPONSE EFFECTS 182
7.7.1 THE GENERAL PROBLEM 182 7.7.2 PLATE AVERAGING (MULTIPLE PLATES)
184 7.7.3 MEDIAN POLISH SMOOTHING (SINGLE PLATES, MULTIPLE PLATES) 185
7.7.4 CHANGE POINT DETECTION (MULTIPLE PLATES, PLATE SEQUENCES) 186
7.7.5 PARAMETRIC (POLYNOMIAL) SURFACE FITTING (SINGLE PLATES, MULTIPLE
PLATES) 187 7.7.6 NONPARAMETRIC SURFACE FITTING, LOCAL REGRESSION, AND
SMOOTHING (SINGLE PLATES, MULTIPLE PLATES) 389 7.7.7 EXPANSION INTO
ORTHOGONAL BASIS FUNCTIONS (SINGLE PLATES) 190 7.7.8 EMPIRICAL
ORTHOGONAL FUNCTION (EOF) ANALYSIS, SINGULAR VALUE DECOMPOSITION (SVD)
(MULTIPLE PLATES) 191 7.7.9 SOME REMARKS ON THE CORRECTION OF INDIVIDUAL
PLATES VERSUS COMPLETE PLATE SETS 194 7.7.10 POSITION-DEPENDENT
CORRECTION OF BACKGROUND RESPONSE SURFACE 195 7.8 HIT IDENTIFICATION AND
HIT SCORING 199 7.9 CONCLUSION 201 8 CHEMOINFORMATIC TOOLS FOR
HIGH-THROUGHPUT SCREENING DATA ANALYSIS PETER C. NELL AND STEFAN M.
MUNDT 8.1 INTRODUCTION 207 8.1.1 DEFINITION OF CHEMOINFORMATICS 208
8.1.2 HIGH-THROUGHPUT SCREENING 208 8.1.2.1 RANDOM SCREENING 209 8.1.2.2
SEQUENTIAL SCREENING 209 8.2 WORKFLOW OF HIGH-THROUGHPUT SCREENING AND
USE OF CHEMOINFORMATICS 211 8.3 CHEMOINFORMATIC METHODS USED IN HTS
WORKFLOW 214 8.3.1 SUBSTRUCTURE SEARCH/SIMILARITY SEARCH 214 8.3.1.1
STRUCTURAL DESCRIPTORS/FINGERPRINTS 215 8.3.1.2 MEASURES OF SIMILARITY
217 8.3.2 CLUSTERING 218 8.3.2.1 HIERARCHICAL CLUSTERING 219 8.3.2.2
NONHIERARCHICAL CLUSTERING 219 8.3.2.3 PARTITIONING METHODS 220 8.3.2.4
PRINCIPAL COMPONENTS ANALYSIS 221 8.3.3 MAXIMUM COMMON SUBSTRUCTURE -
DISTILL 222 XII LIST OF CONTENTS 8.3.4 MODE OF ACTION-PROFILING 223
8.3.5 ARTIFICIAL NEURAL NETWORKS (ANNS) 224 8.3.6 DECISION
TREES/RECURSIVE PARTITIONING 226 8.3.7 REDUCED GRAPH-BASED METHODS 226
8.3.7.1 REDUCED GRAPH THEORY ANALYSIS: BAYTREE 227 8.3.8 FRAGMENT-BASED
METHODS - STRUCTURAL UNITS ANALYSIS 230 8.4 CHEMOINFORMATIC METHODS IN
THE DESIGN OF A SCREENING LIBRARY 8.4.1 DRUG AND LEAD LIKENESS 231 8.4.2
ADME PARAMETERS 233 8.4.2.1 ABSORPTION 233 8.4.2.2 DISTRIBUTION 234
8.4.2.3 METABOLISM 234 8.4.2.4 EXCRETION 235 8.4.2.5 TOXICITY 235 8.4.3
DIVERSITY 236 8.5 INTEGRATED SOFTWARE PACKAGES 238 8.5.1 COMMERCIALLY
AVAILABLE PACKAGES 239 8.5.1.1 ACCELRYS: DIVA 239 8.5.1.2 BIOSOLVELT:
HTSVIEW 239 8.5.1.3 SCITEGIC: PIPELINE PILOT* 240 8.5.1.4 BIOREASON:
CLASSPHARMER* SUITE 241 8.5.1.5 SPOTFIRE LEAD DISCOVERY 242 8.5.1.6
LEADSCOPE 243 8.5.1.7 OMNIVIZ 244 8.5.1.8 SARNAVIGATOR 245 8.5.2
IN-HOUSE PACKAGES 246 8.6 CONCLUSIONS 247 231 9 COMBINATORIAL CHEMISTRY
AND HIGH-THROUGHPUT SCREENING ROGER A. SMITH AND NILS CRIEBENOW 9.1
INTRODUCTION 259 9.2 CATEGORIES OF COMPOUND LIBRARIES FOR
HIGH-THROUGHPUT SCREENING 9.3 SYNTHESIS TECHNIQUES AND LIBRARY FORMATS
261 9.3.1 SOLID-PHASE SYNTHESIS 262 9.3.1.1 PARALLEL SOLID-PHASE
SYNTHESIS TECHNIQUES AND TOOLS 265 9.3.1.2 POOL/SPLIT TECHNIQUES WITH
ENCODING 265 9.3.2 SOLUTION-PHASE SYNTHESIS 269 9.3.2.1
POLYMER-SUPPORTED REAGENTS AND SCAVENGERS 269 9.3.2.2 EXTRACTION
TECHNIQUES FOR PURIFICATION 271 9.3.2.3 PURIFICATION BY CHROMATOGRAPHY
273 9.3.3 LIBRARY FORMATS 273 9.3.3.1 ONE-BEAD ONE-COMPOUND LIBRARIES
274 9.3.3.2 PRE-ENCODED LIBRARIES 275 9.3.3.3 SPATIALLY ADDRESSABLE
LIBRARIES 276 9.4 LIBRARY DESIGN AND PROFILING APPROACHES 277 260 LIST
OF CONTENTS XIII 9.5 IMPACT OF COMBINATORIAL LIBRARIES ON DRUG DISCOVERY
277 9.5.1 LEAD IDENTIFICATION 278 9.5.2 LEAD OPTIMIZATION 283 9.5.3
CLINICAL DRUG CANDIDATES 286 9.6 CONCLUSION 290 10 HIGH-THROUGHPUT
SCREENING AND DATA ANALYSIS JEREMY S. CALDWELL AND JEFF JANES 10.1
INTRODUCTION 297 10.2 ANALYSIS OF CELLULAR SCREENING DATA 298 10.2.1
QUALITY CONTROL AND ANALYSIS 298 10.2.2 ENRICHMENT FOR HITS 301 10.2.3
META-DATA ANALYSIS 302 10.3 MASSIVELY PARALLEL CELLULAR SCREENS 305
10.3.1 DATA ANALYSIS OF MULTIDIMENSIONAL DATASETS 307 10.3.2
MULTIDIMENSIONAL CELLULAR PROFILING FOR MOA PREDICTION 311 10.3.3
CELLULAR PROFILING IN LEAD EXPLORATION 314 10.4 SYSTEMATIC SERENDIPITY
317 10.5 CONCLUSION 320 APPENDIX 323 INDEX 333
|
| adam_txt |
HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY EDITED BY JOERG HUESER WILEY-
VCH WILEY-VCH VERLAG GMBH & CO. KGAA VII LIST OF CONTENTS PREFACE XIV
LIST OF CONTRIBUTORS XVI PART I CONCEPT OF SCREENING 1 CHEMICAL
GENETICS: USE OF HIGH-THROUGHPUT SCREENING TO IDENTIFY SMALL-MOLECULE
MODULATORS OF PROTEINS INVOLVED IN CELLULAR PATHWAYS WITH THE AIM OF
UNCOVERING PROTEIN FUNCTION SA L CHIANG 1.1 INTRODUCTION 1 1.2 CLASSICAL
AND CHEMICAL GENETICS 1 1.2.1 FORWARD AND REVERSE SCREENS 3 1.3
IDENTIFYING BIOACTIVE MOLECULES 4 1.4 TARGET IDENTIFICATION 5 1.4.1
HYPOTHESIS-DRIVEN TARGET IDENTIFICATION 5 1.4.2 AFFINITY-BASED TARGET
IDENTIFICATION 6 1.4.3 GENOMIC METHODS OF TARGET IDENTIFICATION 7 1.4.4
PROTEOMIC METHODS 9 1.5 DISCOVERY FOR BASIC RESEARCH VERSUS
PHARMACOTHERAPY GOALS 10 1.6 CHEMICAL GENETIC SCREENS IN THE ACADEMIC
SETTING 11 1.7 CONCLUSIONS 12 2 HIGH-THROUGHPUT SCREENING FOR TARGETED
LEAD DISCOVERY JOERG HUESER, EMANUEL LOHRMANN, BERND KALTHOF, NIK
BURKHARDT, ULF BRUEGGEMEIER, AND MARTIN BECHEM 2.1 CHEMICAL LIBRARIES FOR
HIGH-THROUGHPUT SCREENING 15 2.2 PROPERTIES OF LEAD STRUCTURES 17 2.3
CHALLENGES TO HIGH-THROUGHPUT SCREENING 19 2.4 ASSAY TECHNOLOGIES FOR
HIGH-THROUGHPUT SCREENING 21 2.5 LABORATORY AUTOMATION 24 2.6 FROM
TARGET SELECTION TO CONFIRMED HITS - THE HTS WORKFLOW AND ITS VOCABULARY
25 HIGH-THROUGHPUT SCREENING IN DRUG DISCOVERY. EDITED BY JOERG HUESER
COPYRIGHT 2006 WILEY-VCH VERLAG GMBH & CO. KGAA, WEINHEIM ISBN:
3-527-31283-8 VIII LIST OF CONTENTS 2.7 SEPARATING SPECIFIC MODULATORS
FROM OFF-TARGET EFFECTS 2.8 DATA ANALYSIS AND SCREENING RESULTS 32 2.9
CONCLUSIONS 34 PART II AUTOMATION TECHNOLOGIES 29 3.1 3.1.1 3.1.2 3.1.3
3.1.4 3.1.5 3.1.6 3.1.7 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.4.1 3.2.4.2
3.2.4.3 3.2.4.4 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3 3.3.1.4 3.3.1.5
3.3.1.6 3.3.1.7 3.3.1.8 3.3.2 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.4 3.4.1
3.4.2 3.4.3 TOOLS AND TECHNOLOGIES THAT FACILITATE AUTOMATED SCREENING
JOHN COMLEY INTRODUCTION - THE NECESSITY TO AUTOMATE 37 COMPOUND
LIBRARIES 37 TARGETS AND DATA POINTS 38 MAIN ISSUES FACING HTS GROUPS
TODAY 38 BENEFITS OF MINIATURIZATION 39 BENEFITS OF AUTOMATED HTS 39
SCREENING STRATEGIES 40 ULTRA HTS (UHTS) 40 SAMPLE CARRIERS 41 A BRIEF
HISTORY OF THE MICROPLATE 41 MICROPLATE USAGE TODAY 41 MICROPLATE ARRAYS
42 NON-MICROPLATE ALTERNATIVES 43 LABCHIPS 43 LABCDS 43 LABBRICK 44
ARRAYED COMPOUND SCREENING 44 LIQUID HANDLING TOOLS 45 MAIN MICROPLATE
DISPENSE MECHANISMS 45 PIN TOOLS 45 AIR AND POSITIVE DISPLACEMENT 45
PERISTALTIC 46 SOLENOID-SYRINGE 4 7 SOLENOID-PRESSURE BOTTLE 47
CAPILLARY SIPPER 48 PIEZOELECTRIC 48 ACOUSTIC TRANSDUCER 48 HTS LIQUID
HANDLING APPLICATIONS AND DISPENSING TECHNOLOGIES USED 49 BULK REAGENT
AND CELL ADDITION 49 COMPOUND REFORMATTING AND NANOLITER DISPENSING 50
CHERRY PICKING AND SERIAL DILUTION 51 MICROPLATE WASHING 52 DETECTION
TECHNOLOGIES 53 MAIN DETECTION MODALITIES USED IN HTS 53 PLATE READERS
54 PLATE IMAGERS 55 LIST OF CONTENTS IX 3.4.3.1 MACRO-IMAGING 56 3.4.3.2
MICRO-IMAGING 57 3.4.4 DISPENSE AND READ DEVICES 60 3.4.5 OTHER
DETECTION TECHNOLOGIES 60 3.4.6 AUTOMATION OF DETECTION TECHNOLOGIES 61
3.4.7 POTENTIAL SOURCES OF READING ERROR 61 3.5 LABORATORY ROBOTICS 62
3.5.1 TRADITIONAL WORKSTATIONS 64 3.5.2 ROBOTIC SAMPLE PROCESSORS 64
3.5.3 PLATE STORAGE DEVICES 64 3.5.4 PLATE MOVING DEVICES 65 3.5.5 FULLY
INTEGRATED ROBOTIC SYSTEMS 65 3.5.6 TURNKEY WORKSTATIONS 66 3.5.7
AUTOMATED CELL CULTURE SYSTEMS 66 3.5.8 COMPOUND MANAGEMENT SYSTEMS 67
3.5.8.1 CURRENT PRACTICE IN COMPOUND MANAGEMENT 67 3.5.8.2 PLATE-BASED
VERSUS TUBE-BASED LIQUID COMPOUND STORAGE 3.5.8.3 ASSOCIATED AUTOMATED
INSTRUMENTATION 70 3.5.8.4 SAMPLE INTEGRITY AND QC TESTING 70 PART III
ASSAY TECHNOLOGIES FUNCTIONAL CELL-BASED ASSAYS FOR TARGETED LEAD
DISCOVERY IN HIGH-THROUGHPUT SCREENING JOERG HUESER, BERND KALTHOF, AND
JOCHEN STRAYLE INTRODUCTION 75 REPORTER GENE TECHNOLOGIES 78 MEMBRANE
POTENTIAL INDICATORS 82 CA 2+ INDICATORS 88 CONCLUSIONS 90 68 4.1 4.2
4.3 4.4 4.5 5.1 5.2 5.2.1 5.2.2 5.2.3 5.3 5.3.1 5.3.2 5.4 5.4.1
BIOCHEMICAL ASSAYS FOR HIGH-THROUGHPUT SCREENING WILLIAM D. MALLENDER,
MICHAEL BEMBENEK, LAWRENCE R. DICK, MICHAEL KURANDA, PING LI, SAURABH
MENON, ENEIDA PARDO AND TOM PARSONS GENERAL CONSIDERATIONS FOR
BIOCHEMICAL HIGH-THROUGHPUT SCREENING 93 EXPRESSION AND PURIFICATION OF
RECOMBINANT ENZYMES 95 DESIGN OF EXPRESSION CONSTRUCTS 98 EXPRESSION
ASSESSMENT AND OPTIMIZATION 99 PURIFICATION 99 PEPTIDASES 102
APPLICATION OF FLUOROGENIC SUBSTRATES TO CONFIGURE PEPTIDASE SCREENS 102
THE VALUE OF CONTINUOUS ASSAYS 107 OXIDOREDUCTASES 107 NAD(P)-DEPENDENT
OXIDOREDUCTASES 108 X LIST OF CONTENTS 5.4.2 NON-NAD(P)
COFACTOR-DEPENDENT OXIDOREDUCTASES 110 5.4.3 OXIDASES OR
OXYGEN-UTILIZING OXIDOREDUCTASES 111 5.4.4 GENERAL CONSIDERATIONS 113
5.5 TRANSFERASES, SYNTHETASES AND LIPID-MODIFYING ENZYMES 114 5.5.1
STREPTAVIDIN-BIOTIN CAPTURE 114 5.5.2 IONIC CAPTURE 117 5.5.3
HYDROPHOBIC CAPTURE 117 5.6 KINASES 120 5.6.1 STREPTAVIDIN-BIOTIN
CAPTURE 120 5.6.2 HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) 122
5.6.3 PYRUVATE KINASE-LACTATE DEHYDROGENASE ASSAY SYSTEM 122 5.7
PITFALLS AND REASONS FOR ASSAY DEVELOPMENT FAILURES 125 6 IMAGE-BASED
HIGH-CONTENT SCREENING - A VIEW FROM BASIC SCIENCES PETER LIPP AND LARS
KAESTNER 6.1 INTRODUCTION 129 6.2 HCS SYSTEMS EMPLOYING CONFOCAL OPTICAL
TECHNOLOGIES 132 6.3 SINGLE-POINT SCANNING TECHNOLOGY 134 6.4 LINE
SCANNING TECHNOLOGY 136 6.5 MULTI-BEAM TECHNOLOGY 138 6.6 STRUCTURED
ILLUMINATION 145 6.7 SUMMARY AND PERSPECTIVES 147 PART IV DATA ANALYSIS
7 METHODS FOR STATISTICAL ANALYSIS, QUALITY ASSURANCE AND MANAGEMENT OF
PRIMARY HIGH-THROUGHPUT SCREENING DATA HANSPETER CUBLER 7.1 INTRODUCTION
151 7.1.1 OVERVIEW 151 7.1.2 PROBLEMS DURING THE ANALYSIS OF PRIMARY HTS
DATA 151 7.2 STATISTICAL CONSIDERATIONS IN ASSAY DEVELOPMENT 155 7.3
DATA ACQUISITION, DATA PREPROCESSING, AND HTS DATA ANALYSIS ENVIRONMENT
158 7.4 DATA NORMALIZATION 160 7.5 ROBUST STATISTICS IN HTS DATA
ANALYSIS 163 7.5.1 THE GENERAL PROBLEM 163 7.5.2 THRESHOLD SETTING - A
SIMPLE MODEL 164 7.5.3 THRESHOLD SETTING - A COMPLEX MODEL 165 7.5.4 THE
MOST IMPORTANT ROBUST ESTIMATION METHODS FOR DATA SUMMARIES 1 65 7.5.5
AN ILLUSTRATIVE EXAMPLE: PERFORMANCE OF LOCATION AND SCALE ESTIMATORS ON
TYPICAL HTS DATA ACTIVITY DISTRIBUTIONS 167 7.5.6 A ROBUST OUTLIER
DETECTION METHOD 168 7.5.7 OUTLIER-RESISTANT VERSIONS OF SIMPLE HTS DATA
QUALITY INDICATORS 170 LIST OF CONTENTS XI 7.6 MEASURES OF HTS DATA
QUALITY, SIGNALING OF POSSIBLE QC PROBLEMS, VISUALIZATIONS 170 7.6.1
TRENDS AND CHANGE POINTS 171 7.6.2 POSITIONAL EFFECTS - SUMMARY
STATISTICS AND VIEWS 175 7.6.3 POSITIONAL EFFECTS - HEAT MAPS, TRELLIS
PLOTS, AND ASSAY MAPS 177 7.6.4 DISTRIBUTION DENSITIES - HISTOGRAMS,
SMOOTHED DISTRIBUTIONS 180 7.6.5 NUMERICAL DIAGNOSTICS AND FULLY
AUTOMATED QC ASSESSMENT 181 7.6.6 POSSIBLE SOURCES OF SYSTEMATIC ERRORS
AND TRENDS 182 7.7 CORRECTION OF POSITION-DEPENDENT RESPONSE EFFECTS 182
7.7.1 THE GENERAL PROBLEM 182 7.7.2 PLATE AVERAGING (MULTIPLE PLATES)
184 7.7.3 MEDIAN POLISH SMOOTHING (SINGLE PLATES, MULTIPLE PLATES) 185
7.7.4 CHANGE POINT DETECTION (MULTIPLE PLATES, PLATE SEQUENCES) 186
7.7.5 PARAMETRIC (POLYNOMIAL) SURFACE FITTING (SINGLE PLATES, MULTIPLE
PLATES) 187 7.7.6 NONPARAMETRIC SURFACE FITTING, LOCAL REGRESSION, AND
SMOOTHING (SINGLE PLATES, MULTIPLE PLATES) 389 7.7.7 EXPANSION INTO
ORTHOGONAL BASIS FUNCTIONS (SINGLE PLATES) 190 7.7.8 EMPIRICAL
ORTHOGONAL FUNCTION (EOF) ANALYSIS, SINGULAR VALUE DECOMPOSITION (SVD)
(MULTIPLE PLATES) 191 7.7.9 SOME REMARKS ON THE CORRECTION OF INDIVIDUAL
PLATES VERSUS COMPLETE PLATE SETS 194 7.7.10 POSITION-DEPENDENT
CORRECTION OF BACKGROUND RESPONSE SURFACE 195 7.8 HIT IDENTIFICATION AND
HIT SCORING 199 7.9 CONCLUSION 201 8 CHEMOINFORMATIC TOOLS FOR
HIGH-THROUGHPUT SCREENING DATA ANALYSIS PETER C. NELL AND STEFAN M.
MUNDT 8.1 INTRODUCTION 207 8.1.1 DEFINITION OF CHEMOINFORMATICS 208
8.1.2 HIGH-THROUGHPUT SCREENING 208 8.1.2.1 RANDOM SCREENING 209 8.1.2.2
SEQUENTIAL SCREENING 209 8.2 WORKFLOW OF HIGH-THROUGHPUT SCREENING AND
USE OF CHEMOINFORMATICS 211 8.3 CHEMOINFORMATIC METHODS USED IN HTS
WORKFLOW 214 8.3.1 SUBSTRUCTURE SEARCH/SIMILARITY SEARCH 214 8.3.1.1
STRUCTURAL DESCRIPTORS/FINGERPRINTS 215 8.3.1.2 MEASURES OF SIMILARITY
217 8.3.2 CLUSTERING 218 8.3.2.1 HIERARCHICAL CLUSTERING 219 8.3.2.2
NONHIERARCHICAL CLUSTERING 219 8.3.2.3 PARTITIONING METHODS 220 8.3.2.4
PRINCIPAL COMPONENTS ANALYSIS 221 8.3.3 MAXIMUM COMMON SUBSTRUCTURE -
DISTILL 222 XII LIST OF CONTENTS 8.3.4 MODE OF ACTION-PROFILING 223
8.3.5 ARTIFICIAL NEURAL NETWORKS (ANNS) 224 8.3.6 DECISION
TREES/RECURSIVE PARTITIONING 226 8.3.7 REDUCED GRAPH-BASED METHODS 226
8.3.7.1 REDUCED GRAPH THEORY ANALYSIS: BAYTREE 227 8.3.8 FRAGMENT-BASED
METHODS - STRUCTURAL UNITS ANALYSIS 230 8.4 CHEMOINFORMATIC METHODS IN
THE DESIGN OF A SCREENING LIBRARY 8.4.1 DRUG AND LEAD LIKENESS 231 8.4.2
ADME PARAMETERS 233 8.4.2.1 ABSORPTION 233 8.4.2.2 DISTRIBUTION 234
8.4.2.3 METABOLISM 234 8.4.2.4 EXCRETION 235 8.4.2.5 TOXICITY 235 8.4.3
DIVERSITY 236 8.5 INTEGRATED SOFTWARE PACKAGES 238 8.5.1 COMMERCIALLY
AVAILABLE PACKAGES 239 8.5.1.1 ACCELRYS: DIVA 239 8.5.1.2 BIOSOLVELT:
HTSVIEW 239 8.5.1.3 SCITEGIC: PIPELINE PILOT* 240 8.5.1.4 BIOREASON:
CLASSPHARMER* SUITE 241 8.5.1.5 SPOTFIRE LEAD DISCOVERY 242 8.5.1.6
LEADSCOPE 243 8.5.1.7 OMNIVIZ 244 8.5.1.8 SARNAVIGATOR 245 8.5.2
IN-HOUSE PACKAGES 246 8.6 CONCLUSIONS 247 231 9 COMBINATORIAL CHEMISTRY
AND HIGH-THROUGHPUT SCREENING ROGER A. SMITH AND NILS CRIEBENOW 9.1
INTRODUCTION 259 9.2 CATEGORIES OF COMPOUND LIBRARIES FOR
HIGH-THROUGHPUT SCREENING 9.3 SYNTHESIS TECHNIQUES AND LIBRARY FORMATS
261 9.3.1 SOLID-PHASE SYNTHESIS 262 9.3.1.1 PARALLEL SOLID-PHASE
SYNTHESIS TECHNIQUES AND TOOLS 265 9.3.1.2 POOL/SPLIT TECHNIQUES WITH
ENCODING 265 9.3.2 SOLUTION-PHASE SYNTHESIS 269 9.3.2.1
POLYMER-SUPPORTED REAGENTS AND SCAVENGERS 269 9.3.2.2 EXTRACTION
TECHNIQUES FOR PURIFICATION 271 9.3.2.3 PURIFICATION BY CHROMATOGRAPHY
273 9.3.3 LIBRARY FORMATS 273 9.3.3.1 ONE-BEAD ONE-COMPOUND LIBRARIES
274 9.3.3.2 PRE-ENCODED LIBRARIES 275 9.3.3.3 SPATIALLY ADDRESSABLE
LIBRARIES 276 9.4 LIBRARY DESIGN AND PROFILING APPROACHES 277 260 LIST
OF CONTENTS XIII 9.5 IMPACT OF COMBINATORIAL LIBRARIES ON DRUG DISCOVERY
277 9.5.1 LEAD IDENTIFICATION 278 9.5.2 LEAD OPTIMIZATION 283 9.5.3
CLINICAL DRUG CANDIDATES 286 9.6 CONCLUSION 290 10 HIGH-THROUGHPUT
SCREENING AND DATA ANALYSIS JEREMY S. CALDWELL AND JEFF JANES 10.1
INTRODUCTION 297 10.2 ANALYSIS OF CELLULAR SCREENING DATA 298 10.2.1
QUALITY CONTROL AND ANALYSIS 298 10.2.2 ENRICHMENT FOR HITS 301 10.2.3
META-DATA ANALYSIS 302 10.3 MASSIVELY PARALLEL CELLULAR SCREENS 305
10.3.1 DATA ANALYSIS OF MULTIDIMENSIONAL DATASETS 307 10.3.2
MULTIDIMENSIONAL CELLULAR PROFILING FOR MOA PREDICTION 311 10.3.3
CELLULAR PROFILING IN LEAD EXPLORATION 314 10.4 SYSTEMATIC SERENDIPITY
317 10.5 CONCLUSION 320 APPENDIX 323 INDEX 333 |
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| spelling | High-throughput screening in drug discovery ed. by Jörg Hüser High throughput screening in drug discovery Weinheim Wiley-VCH-Verl. 2006 XVIII, 343 S. Ill., graph. Darst. 25 cm txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 35 Literaturangaben. Titel fälschlich auf d. Umschlag: High throughput-screening in drug discovery Criblage à haut débit (Développement des médicaments) Chemistry, Pharmaceutical methods Drug Design Drug Evaluation, Preclinical High throughput screening (Drug development) High throughput screening (DE-588)4596131-1 gnd rswk-swf Arzneimitteldesign (DE-588)4278218-1 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Arzneimitteldesign (DE-588)4278218-1 s High throughput screening (DE-588)4596131-1 s DE-604 Hüser, Jörg edt Methods and principles in medicinal chemistry 35 (DE-604)BV035418617 35 text/html http://deposit.dnb.de/cgi-bin/dokserv?id=2712997&prov=M&dok_var=1&dok_ext=htm Inhaltstext GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=015690587&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | High-throughput screening in drug discovery Methods and principles in medicinal chemistry Criblage à haut débit (Développement des médicaments) Chemistry, Pharmaceutical methods Drug Design Drug Evaluation, Preclinical High throughput screening (Drug development) High throughput screening (DE-588)4596131-1 gnd Arzneimitteldesign (DE-588)4278218-1 gnd |
| subject_GND | (DE-588)4596131-1 (DE-588)4278218-1 (DE-588)4143413-4 |
| title | High-throughput screening in drug discovery |
| title_alt | High throughput screening in drug discovery |
| title_auth | High-throughput screening in drug discovery |
| title_exact_search | High-throughput screening in drug discovery |
| title_exact_search_txtP | High-throughput screening in drug discovery |
| title_full | High-throughput screening in drug discovery ed. by Jörg Hüser |
| title_fullStr | High-throughput screening in drug discovery ed. by Jörg Hüser |
| title_full_unstemmed | High-throughput screening in drug discovery ed. by Jörg Hüser |
| title_short | High-throughput screening in drug discovery |
| title_sort | high throughput screening in drug discovery |
| topic | Criblage à haut débit (Développement des médicaments) Chemistry, Pharmaceutical methods Drug Design Drug Evaluation, Preclinical High throughput screening (Drug development) High throughput screening (DE-588)4596131-1 gnd Arzneimitteldesign (DE-588)4278218-1 gnd |
| topic_facet | Criblage à haut débit (Développement des médicaments) Chemistry, Pharmaceutical methods Drug Design Drug Evaluation, Preclinical High throughput screening (Drug development) High throughput screening Arzneimitteldesign Aufsatzsammlung |
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