High Throughput Screening: The Discovery of Bioactive SubstancesCRC Press, 1997 M05 6 - 704 pages Furnishing the latest interdisciplinary information on the most important and frequently the only investigational system available for discovery programs that address the effects of small molecules on newly discovered enzyme and receptor targets emanating from molecular biology, this timely resource facilitates the transition from classical to high throughput screening (HTS) systems and provides a solid foundation for the implementation and development of HTS in bio-based industries and associated academic environments. |
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Contents
CHEMICAL DIVERSITY AND GENETIC EQUITY SYNTHETIC AND NATURALLY DERIVED COMPOUNDS | 3 |
DIVERSITY IS THE KEY | 4 |
3 COMMERCIAL COMPOUND PURCHASES | 5 |
4 NATURAL PRODUCTS | 7 |
RICH RESOURCE OR CURIOSITY? | 13 |
7 CONCLUSIONS | 16 |
TEST SUBSTANCE SOURCES | 17 |
CONVENTION ON BIOLOGICAL DIVERSITY1992 | 22 |
HOMOGENEOUS TIMERESOLVED FLUORESCENCE METHOD FOR DRUG DISCOVERY | 345 |
2 THE THEORY OF HTRF | 346 |
3 APPLICATIONS OF HTRF | 349 |
4 INSTRUMENTATION AND ROBOTICS | 358 |
TIMERESOLVED FLUOROMETRY ADVANTAGES AND POTENIALS | 361 |
2 FLUOROMETRY | 362 |
3 LANTHANIDES AS FLUORESCENT PROBES | 367 |
4 TIMERESOLVED FLUOROMETRY IN BIOMEDICAL RESEARCH | 372 |
CLINTON ADMINISTRATION PROPOSED INTERPRETATION | 43 |
INTERNET ACCESS TO NATURAL PRODUCT INFORMATION | 48 |
MICROCOLLECTION OF PLANTS FOR BIOCHEMICAL PROFILING | 49 |
2 BOTANICAL AND CHEMICAL DIVERSITY | 51 |
3 COLLECTION SCOPE | 53 |
4 VOUCHER SAMPLING STORAGE AND RETRIEVAL | 54 |
5 MICROCOLLECTION TECHNIQUES | 56 |
6 DATA MANAGEMENT AND SAMPLE PREPARATION | 61 |
7 EXTRACTION PROCESSES | 63 |
8 REMOVAL OF INTERFERING SUBSTANCES | 64 |
9 TEST SAMPLE PREPARATIONS IN MICROPLATE FORMAT | 68 |
10 FOLLOWUP AND RECOLLECTION | 69 |
11 CHEMOTAXONOMY AND PHYTOCHEMICAL TRACKING | 72 |
12 CONCLUSIONS | 75 |
ENZYMES AND MICROBES AS A SOURCE OF CHEMICAL DIVERSITY | 77 |
2 THE PRODUCTION OF CHEMICALS BY MICROBIAL FERMENTATION | 80 |
3 PRODUCTION OF CHEMICALS BY IMMOBILIZED MICROORGANISMS | 85 |
4 FOREIGN PROTEIN SYNTHESIS BY MICROORGANISMS | 90 |
5 STEROID TRANSFORMATIONS BY MICROORGANISMS | 92 |
7 THE FUTURE | 95 |
THE MARINE ENVIRONMENT AS A DISCOVERY RESOURCE | 99 |
2 SCOPE AND DIVERSITY | 103 |
3 ACCESS TO MARINE NATURAL PRODUCTS LIBRARIES | 114 |
4 ECONOMIC CONCERNS | 116 |
5 REQUIREMENTS OF AN EFFECTIVE ACQUISITION PROGRAM | 118 |
6 ECOLOGICAL CONCERNS | 125 |
7 SCALEUP DEVELOPMENT ALTERNATIVES | 127 |
8 CONCLUSIONS | 133 |
COMPOUND SOURCING CHEMICALLY GENERATED SCREENING LIBRARIES | 145 |
INTRODUCTION | 147 |
2 SOLID PHASE ORGANIC CHEMISTRY | 148 |
4 PARALLEL SYNTHESIS OF INDIVIDUAL COMPOUNDS | 150 |
5 AUTOMATION | 153 |
RAPIDLY EXPANDING MOLECULAR DIVERSITY LIBRARIES FROM LIBRARIES | 155 |
2 LIBRARY PREPARATION | 156 |
3 DECONVOLUTION METHODS FOR NONSUPPORTBOUND COMBINATORIAL LIBRARIES | 157 |
4 SOLUBLE COMBINATORIAL LIBRARIES | 158 |
5 CONCLUSION | 164 |
SYNTHESIS OF ENCODED SMALL MOLECULE COMBINATORIAL LIBRARIES VIA ECLiPS | 167 |
2 ECLiPS TECHNOLOGY | 172 |
3 ENCODED SMALL MOLECULE COMBINATORIAL LIBRARIES | 175 |
4 CONCLUSION | 188 |
PARALLEL ORGANIC SYNTHESIS USING PARKDAVIS DIVERSOMER METHOD | 191 |
2 ORGANIC SYNTHESIS ON SOLIDSUPPORT | 192 |
3 THE DIVERSOMER APPARATUS | 194 |
4 ROBOTIC INTERFACING | 195 |
5 EXAMPLES OF DIVERSOMER SYNTHESES | 196 |
6 INFORMATION MANAGEMENT | 204 |
RAPID DISCOVERY AND OPTIMIZATION OF BIOLOGICALLY ACTIVE SMALL MOLECULES USING AUTOMATED SYNTHESIS METHODS | 209 |
3 ONTOGEN COMPOUND LIBRARIES | 214 |
4 CONCLUSION | 219 |
CMT A SOLUTION PHASE COMBINATORIAL CHEMISTRY APPROACH SYNTHESIS AND YIELD PREDICTION OF PHENAZINES | 223 |
CONCEPT AND PHILOSOPHY | 224 |
3 EXPERIMENTAL | 231 |
4 DISCUSSION | 240 |
DESIGN OF A DIVERSE SCREENING LIBARY | 243 |
2 MATRIX CHEMISTRY | 244 |
3 DIVERSITY OBJECTIVES | 245 |
4 DESIGN PARAMETERS | 247 |
5 EXAMPLE OF DESIGNED DIVERSITY | 249 |
6 SUMMARY | 250 |
AUTOMATING COMBINATORIAL CHEMISTRY CHALLENGES AND PITFALLS | 251 |
COMBICHEM HIGH THROUGHPUT SCREENING FOR LEADS OPTIMIZATION | 263 |
2 SAMPLE SCREENING RESULTS | 264 |
3 CONCLUSIONS | 269 |
4 SUMMARY | 270 |
ASSAY TECHNOLOGIES AND DETECTION METHODS | 273 |
INTRODUCTION | 275 |
1 USING MORE EFFICIENT ASSAY METHODS TO REDUCE COMPROMISES IN SCREENING | 276 |
2 THE DIVERSITY OF HTS METHODS | 278 |
BIOASSAY DESIGN AND IMPLEMTATION | 279 |
2 TARGET SELECTION | 280 |
3 TYPES AND CHARACTERISTICS OF SCREENING ASSAYS | 285 |
4 DECISION MAKING | 302 |
SCINTILLATION PROXIMITY ASSAYS | 307 |
2 AUTOMATABILITY OF SPA SCREENING ASSAYS | 308 |
3 ASSAY THROUGHPUT USING SPA | 310 |
4 NUMBER OF HITS IN SPA HTS ASSAYS | 311 |
6 SIGNAL TO NOISE RATIOS UTILIZED IN SPA HTS ASSAYS | 313 |
8 TYPES OF COMPOUND LIBRARIES TESTED WITH SPA | 314 |
10 TYPES OF SCINTILLATION COUNTER USED WITH SPA | 315 |
FLASHPLATE TECHNOLOGY | 317 |
2 RECEPTOR BINDING ASSAYS ON FLASHPLATE | 319 |
3 LIVE CELL ASSAYS ON FLASHPLATE | 320 |
4 ENZYME ASSAYS ON FLASHPLATE | 321 |
5 RADIOIMMUNOASSAYS ON FLASHPLATE | 326 |
6 SUMMARY | 327 |
ASSAYS FOR SMALL MOLECULE AGONISTS AND ANTAGONISTS OF THE NEUROTROPHIN RECEPTORS | 329 |
2 RECEPTOR BINDING ASSAY | 331 |
3 RECEPTOR ACTIVATION ASSAY | 334 |
4 ASSAY AUTOMATION | 341 |
5 AUTOMATION | 373 |
ADAPTATION OF TIMERESOLVED FLUORESCENCE TO HOMOGENEOUS SCREENING FORMAT | 377 |
2 MATERIALS AND METHODS | 378 |
3 RESULTS AND DISCUSSION | 381 |
4 SUMMARY OF ADVANTAGES | 387 |
FLUORESCENCE POLARIZATION | 389 |
2 THE POTENTIAL OF FLUORESCENCE POLARIZATION | 390 |
4 INSTRUMENTATION | 392 |
6 ASSAY CHARACTERISTICS | 394 |
8 CHALLENGES IN HIGH THROUGHPUT SCREENING BY FP | 396 |
REPORTER GENE ASSAY APPLICATIONS | 401 |
2 REPORTER GENES AND THEIR PRODUCTS | 402 |
3 DETECTION TECHNIQUES AND THEIR IMPROVEMENT | 405 |
4 FUTURE ASPECTS | 406 |
DEVELOPMENT OF A GENE EXPRESSIONBASED SCREEN USING QUANTITATIVE POLYMERASE CHAIN REACTION | 413 |
3 DEVELOPMENT OF A GENE EXPRESSIONBASED SCREEN GEBS | 415 |
4 THROUGHPUT OF GEBS | 422 |
HIGHPERFORMANCE MICROPHYSIOMETRY IN DRUG DISCOVERY | 427 |
2 SUMMARY OF MICROPHYSIOMETRY | 428 |
3 BIOLOGICAL ISSUES | 429 |
4 HIGHPERFORMANCE MICROPHYSIOMETRY | 433 |
5 FUTURE EXTENSIONS OF MICROPHYSIOMETRY | 439 |
6 CONCLUSION | 440 |
BIOanalytical APPLICATIONS OF BIAcore an OPTICAL BIOSENSOR | 443 |
2 SYSTEM DESIGN | 444 |
3 APPLICATIONS | 446 |
4 CONCLUSIONS | 452 |
AUTOMATION AND ROBOTICS | 455 |
Introduction | 457 |
2 THE FUTURE OF AUTOMATION AND ROBOTICS | 458 |
MANAGEMENT AND SERVICE ISSUES OF A CENTRALIZED ROBOTIC HTS CORE | 461 |
2 SENIOR MANAGEMENT PERCEPTIONS AND EXPECTATIONS | 462 |
3 BALANCING NEW TECHNOLOGY DEVELOPMENT AND DATA PRODUCTION | 464 |
4 COPING WITH THE MONOTONY OF SCREENING | 466 |
5 WORKING WITH SCIENTIST CUSTOMERS | 467 |
6 SUMMARY | 468 |
FLEXIBLE USE OF PEOPLE AND MACHINES | 471 |
2 APPROACHES TO AUTOMATION IN HTS | 472 |
4 IMPLEMENTING AN AUTOMATION PROJECT | 477 |
5 FUTURE PROSPECTS FOR AUTOMATION IN HTS | 480 |
BARCODE TECHNOLOGY AND A CENTRALIZED DATABASE KEY COMPONENTS IN A RADIOLIGAND BINDING PROGRAM | 483 |
2 METHODS | 484 |
3 DISCUSSION | 490 |
4 GLOSSARY OF TERMS | 491 |
FACTORS FOR THE SUCCESSFUL INTEGRATION OF ASSAYS EQUIPMENT ROBOTICS AND SOFTWARE | 493 |
2 DEFINING THE SCREENING OBJECTIVES | 494 |
4 HARDWARE | 497 |
5 COMPUTING | 500 |
6 FURTHER DEVELOPMENT OF THE HTS FACILITY | 504 |
ACCELERATING THE DISCOVERY PROCESS WITH AUTOMATION AND ROBOTICS A SURE BET OR A RISKY VENTURE? | 509 |
2 BACKGROUND | 510 |
3 CRITICAL SUCCESS FACTORS | 512 |
4 EXAMPLES | 522 |
5 CONCLUSIONS | 523 |
PERSPECTIVES ON SCHEDULING | 525 |
2 SCHEDULING | 526 |
3 COMMUNICATION TOOLS | 535 |
4 USER INTERFACE | 539 |
5 CONCLUSION | 544 |
DATA RETRIEVAL HANDLING AND INTEGRATION | 547 |
Introduction | 549 |
DATABASE SYSTEMS | 551 |
3 CLIENTSERVER SYSTEMS | 564 |
4 PERFORMANCE AND DESIGN CONSIDERATIONS | 571 |
5 CHEMICAL STRUCTURE DATABASES | 579 |
6 PROGRAMMING CONSIDERATIONS | 580 |
7 FINAL SUMMARY POINTS | 581 |
SYSTEMS INTEGRATION | 583 |
2 HTS DATA MANAGEMENT | 584 |
3 CONCLUSION | 596 |
DATA MANAGEMENT AND TRACKING FOR NATURAL PRODUCT PROGRAMS | 599 |
2 USER REQUIREMENTS | 603 |
3 IMPLEMENTING AN EFFECTIVE SYSTEM | 612 |
4 CONCLUSIONS | 619 |
LABORATORY DESIGN AND MANAGEMENT | 623 |
INTRODUCTION | 625 |
PLANNING AND IMPLEMENTING AN HTS PROGRAM | 627 |
3 PROGRAM LOGISTICS | 632 |
4 ASSAYS | 635 |
5 SAMPLES | 639 |
6 RESOURCING | 644 |
7 MANAGEMENT CONSIDERATIONS | 651 |
ESTABLISHING AND HTS PROGRAM INA STARTUP BIOTECHNOLOGY COMPANY | 653 |
2 PLANNING THE SCREENING PROGRAM | 655 |
3 SAMPLES FOR SCREENING | 656 |
4 EQUIPPING THE HTS LABORATORY | 658 |
5 DEVELOPING HIGH THROUGHPUT SCREENS | 660 |
6 REAGENT SUPPLY | 661 |
8 LEAD DISCOVERY | 666 |
669 | |
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High Throughput Screening: The Discovery of Bioactive Substances John P. Devlin Limited preview - 1997 |
Common terms and phrases
acid actinomycetes activity analysis antibody applications approach assay assay plate bar-code BIAcore binding assay biochemical biological diversity cells chelates Chem chemical diversity collection combinatorial chemistry combinatorial libraries companies components compounds concentration Contracting Party cryptate database detection DMSO drug discovery enzyme evaluated example extracts Figure FlashPlate fluorescence format function gene handling high throughput screening HTRF HTS program identified immunoassays implementation incubation inhibition inhibitors instruments integrated interface labeled laboratory large numbers ligand luciferase marine natural products methods microbial microorganisms microplate molecular molecules neurotrophin operation optimization Oracle peptide performed pharmaceutical polyphenols protein protocol radioligand reaction reagents receptor relational database reporter gene resin robotic system samples scintillation screening data screening program secondary metabolites signal solid phase solution specific streptavidin structure substrate synthesis synthetic Table target trkB workstations