Integrated Drug Discovery Technologies 1st Edition by Houng Yau Mei, Anthony W Czarnik ISBN 0824706498 9780824706494

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ISBN 10: 0824706498 
ISBN 13: 9780824706494
Author: Houng Yau Mei, Anthony W Czarnik

Integrated Drug Discovery Technologies 1st Table of contents:

1 The Motivation: A Top-Down View
References
2 Target Identification and Validation: Coupling Genotype to Phenotype
I. Introduction
II. Target Identification/Validation
A. Genomics
1. Genetic Mapping and Positional Cloning
2. Genome Sequencing
3. Functional Genomics
4. Model Organisms (Yeast, C. elegans, Drosophila, Mouse, Rat)
B. Proteomics
C. Pharmacogenetics and Pharmacogenomics
D. Bioinformatics/Structural Informatics/Chemi-informatics
III. Conclusion
References
3 Functional Genomics
I. Introduction
II. Proteins: Structure and Function
A. Molecular Evolution
B. Sequence and Protein Families
III. Molecular Pathways
A. Signal Transduction
B. Protein–Protein Interaction
C. Tertiary Structure and Convergence
D. Gene Expression and Protein Kinetics
E. Autoregulation of Gene Expression
IV. Genomics Techniques
A. High-Throughput Screening
B. Microarrays
C. Single-Nucleotide Polymorphism Detection
D. Deletion Detection
E. Differential Display by Hybridization
F. Expression Monitoring
G. Finding Targets for Drug Development
V. Summary
References
4 Integrated Proteomics Technologies
I. Introduction
II. Gel Electrophoresis
A. Two-Dimensional Gel Electrophoresis
B. Staining Methods in 2-DE
1. Coomassie Stains
2. Silver Staining
3. Fluorescent Stains
C. Imaging and Image Analysis
D. Protein Spot Excision
III. Protein Identification
A. General Concepts
B. Automated Proteolytic Digestion
C. Peptide Mapping by MALDI-MS
D. HPLC-MS and Tandem Mass Spectrometry
E. Computer-Based Sequence Searching Strategies
1. Searching with Peptide Fingerprints
2. Searching with Sequence Information
3. Searching with Raw MS/MS Data
F. Other Methods Used for Proteomics Research
IV. Conclusions
References
5 Where Science Meets Silicon: Microfabrication Techniques and Their Scientific Applications
I. Introduction
II. Traditional Methods of Microfabrication
A. Lithography and Photolithography
1. Bulk Micromachining
2. Surface Micromachining
3. Metal Electrodeposition
B. Newer Techniques and Materials
1. Plasma and Deep Reactive Ion Etching
2. X-ray LIGA
3. UV LIGA
4. Polymer Replication
5. Laser Ablation
6. Ion Beam Milling
7. Ultraprecision Machining
8. Porous Silicon as a Sensor Material
III. System Integration Issues
A. Interfaces
B. Fluidics and Electronic Integration
C. Integral Detection Systems
IV. APPLICATIONS OF MICROTECHNOLOGIES
A. Bead-based Fiberoptic Arrays
B. DNA Arrays
C. Electronically Enhanced Hybridization
1. Electronic Addressing
2. Electronic Concentration and Hybridization
3. Electronic Stringency Control
D. Microfluidic Devices
1. Microfluidic Separations
2. Microfluidic Synthesis
3. Chip-Based Flow Cytometry for Medical Diagnostics
4. Microfluidics in a Rotating CD
V. Nanotechnology
VI. Summary
References
6 SNP Scoring for Drug Discovery Applications
I. Introduction
A. SNP Applications
B. SNP Discovery and Scoring
II. General Considerations
A. Sample Preparation
B. Sample Analysis
C. Automation and Multiplexing
III. SNP Scoring Chemistries
A. Sequencing
B. Hybridization
C. Allele-Specific Chain Extension
D. Single-Base Extension
E. Oligonucleotide Ligation
F. Nuclease-Based Assays
G. Summary
IV. platforms
A. Electrophoresis
B. Microplate-Based Assays
C. Mass Spectrometry
D. Flat Microarrays
E. Soluble Arrays
F. Summary
V. Conclusions and Prospects
References
7 Protein Display Chips
I. Introduction To Protein Chip Technologies
II. Surface Plasmon Resonance Based Technology: How Optical Biosensors Revolutionized Protein–Protein Interaction Studies
A. Optical Biosensor Technology: Technical Background and Development
B. Types of SPR Applications and Experimental Considerations
C. SPR in the Drug Development Process: Conclusion and Outlook
III. Time-Of-Flight Mass Spectrometry–Based Technologies: From Maldi To Seldi and BIA/MS
A. Matrix-Assisted Desorption Techniques: Technical Background and Development History
B. Surface-Enhanced Laser Desorption/lonization (SELDI): Protein Display Chips for Mass Spectrometry
C. SELDI Applications: General Principles and Experimental Considerations
D. SELDI in the Drug Development Process: A Bright Future
E. BIA/MS: Connecting a Popular SPR Platform to MALDI-TOF
IV. Conclusion: Protein Display Chips In Drug Discovery—The Future Is Here
References
8 Integrated Proteomics Technologies and In Vivo Validation of Molecular Targets
I. Proteomics in Molecular Medicine
A. Proteome Terminology
B. Genome vs. Proteome
C. Changes in PTMs Associated with Pathogenesis
D. New Drug Candidates Directed Against Molecular Targets Modulating Protein PTM
E. Protein Expression Mapping
F. Cellular Proteomics
G. Proteomic Analysis of Body Fluids
H. Analyses of Protein Complexes
I. Combined MRNA/Protein Expression Analysis for Pathway Mapping and Candidate Target Selection
II. In Vivo Validation of Molecular Targets
A. Disease Model Relevance
B. Animal Models of Alzheimer’s Disease
C. Animal Models of Cancer
D. Knockout and Mutagenesis Models, and Tissue-Specific Inducible Gene In Vivo Models
E. Gene-Related Functional Proteomics
F. Pharmacoproteomics
III. Proteomic Technology in the Molecular Characterization of Novel Therapeutic Targets: Future Perspectives
Acknowledgments
References
9 High-Throughput Screening as a Discovery Resource
I. Background
II. Where We Are
III. Test Substance Supply
A. Compound Library Development
B. HTOS Applications
C. Natural Products as a Discovery Resource
D. Structure-Based Design
IV. Bioassay Development and Implementation
A. Fluorescence Detection Systems
B. Comparative Functional Genomics
C. ADME and Toxicological Profiling
V. Informatics
VI. Management and Personnel Issues
VII. PROJECTIONS
References
10 Fluorescence Correlation Spectroscopy (FCS) and FCS-Related Confocal Fluorimetric Methods (FCS+plus): Multiple Read-Out Options for Miniaturized Screening
I. Introduction: A Rationale for New Read-Out Methods in Drug Discovery
II. Single-Molecule Confocal Fluorescence Detection Technology
A. FCS+plus: Multiparameter Fluorescence Read-out Technology
B. Advantages of Using FCS+plus for Miniaturized HTS
1. Inherent Miniaturization
2. Homogeneous Assay Format
3. Increased Safety of Reagents
4. Elimination of Background Effects
5. Single-Component Labeling
6. Multiple Read-out Modes
7. Multiple Read-out Parameters
8. Throughput
C. Case Studies I: Using FCS+plus Multiparameter Read-outs
D. Case Studies II: Flexibility of Multiple Read-out Modes
1. Enzyme Assays
2. GPCR Assays
3. Cellular Assays
III. Summary
Acknowledgments
References
11 Homogeneous Time-Resolved Fluorescence
I. Introduction to Homogeneous Time-Resolved Fluorescence
II. Unique Properties of HTRF Chemistry
A. Specific Requirements of Homogeneous Assays
1. Unique Tracers
2. Signal Modulation
3. Resistance to Biological Media
B. Lanthanide Cryptates: A New Type of Fluorescent Label
1. Chelates as Fluorescent Labels
2. Cryptates as Fluorescent Labels
3. Use of XL665 as Acceptor
4. Signal Amplification of the Cryptate Fluorescence
C. HTRF Signal and Measurement
1. Time-Resolved Measurement
2. Dual-Wavelength Measurement
3. Data Reduction
III. APplications of HTRF For High-Throughput Screening
A. Immunoassays
B. Enzyme Assays
C. Receptor Binding Assays
D. Protein–Protein Interactions
E. Nucleic Acid Hybridizations
1. DNA Nuclease Assay
2. Reverse Transcriptase Assay
IV. HTRF Assay Optimization
A. Buffer Selection and Stability
B. Choice of Label for Each Assay Component
C. Suggested Assay Controls
V. Conclusion
References
12 ADME-Tox Screening in Drug Discovery
I. Introduction
A. Why Drugs Fail in the Clinic
B. Challenges with Accurate Prediction of Human Drug Properties
C. Optimization of Drug Properties
II. Experimental Systems for the Optimization of Adme-Tox Properties
A. Intestinal Absorption
1. In Vitro Models for the Prediction of Intestinal Permeability
2. Caco-2 Screening Assay for Intestinal Absorption
B. Drug Metabolism
1. Drug Metabolism Pathways
2. In Vitro Hepatic Experimental Systems for Drug Metabolism
3. Screening Assays for Metabolic Stability
III. Toxicology
A. Screening Assays for Human Hepatotoxicity
B. Other Cytotoxicity Screening Assays
IV. Drug-Drug Interactions
A. Screening for Enzyme Inhibition
B. Screening for Enzyme Induction
V. Future Approaches
VI. Conclusions
References
13 Screening Lead Compounds in the Postgenomic Era: An Integrated Approach to Knowledge Building from Living Cells
I. Introduction
II. Genomics and Proteomics as the Foundation for Cell-Based Knowledge
III. Creation of New Biological Knowledge
IV. HCS of Target Activity in Living Cells
V. HCS of Drug-Induced Microtubule Cytoskeleton Reorganization
VI. Specialized Fluorescent Reagents That Find Dual Use In HCS and HTS
VII. Coupling High-Throughput and High-Content Screening with Microarrays of Living Cells: The Cellchip™ System
VIII. Cellomics Knowledgebase Embodies A New Paradigm for Bioinformatics: Creation of Knowledge From HCS
IX. Prospectus
Acknowledgments
References
14 Miniaturization Technologies for High-Throughput Biology
I. Introduction
A. Key Integrated Miniaturization Technologies
B. Why Is miniaturization Critical to Ultrahigh-Throughput Screening Development?
II. The Screening Process
A. Assay Development
B. Compound Distribution
C. Loading the Assay
D. Incubation
E. Detection
F. Results Database
III. Plate Design and Performance
IV. Microfluidic Technology
A. Sample Distribution Robot System
1. Piezo-actuated Dispensers and the Piezo Sample Distribution Robot
V. Solenoid-Based Dispenser Technology
A. The Reagent Distribution Robot
1. Solenoid-Controlled Liquid Dispensing
2. High-Throughput Liquid Dispensing to Multiple Reaction Wells
VI. Fluorescence Detection
VII. High-Throughput Functional Biology
VIII. Summary
15 Data Management for High-Throughput Screening
I Introduction
A. Background
B. Issues in HTS Data Management
1. Large Volumes of Data
2. Addition of Automation
3. Variability Inherent in Biological Experiments
II. Acquisition Of Data
A. Integration with Automation Equipment
B. Integration with Other Information Systems
C. Well Types and Plate Layouts
D. Calculation, Reduction, and Normalization of Data
1. Percent Inhibition and Percent of Control
III. Validation Of Experimental Results
A. Detection of Experimental Error
B. False Positives vs. False Negatives
C. Sources of Error
1. Automation Equipment Failure
2. Stability of Reagents or Targets
3. Environmental Issues
IV. Decision Support
A. Finding Systematic Error
1. Use of Controls and References
2. Search for Patterns
B. Locating Hits Quickly
1. Evaluating a Single Run or an Entire Campaign
C. Integration of Other Data
D. Graphical Display vs. Tabular Display
1. Tabular Display
2. Graphical Display
E. Reporting
V. DATA ANALYSIS AND MINING
A. Cross-Assay Reports
1. Pivoted Data
2. Classical Structure Activity
B. Visualization of Data
VI. Logistics
A. Plate Handling
B. Special Cases
1. Consolidation
2. Format Changes
3. Pooling/Deconvolution
VII. Conclusion and Future Technologies
A. Higher Densities and Ultrahigh-Throughput Screening
B. Wider Use of HTS Techniques
C. HTS Kinetics and High-Content Screening
D. Conclusion
16 Combinatorial Chemistry: The History and the Basics
I. Definition
II. History
III. Small Organic Molecules
IV. Synthetic Techniques
V. Philosophy and Criteria
References
17 New Synthetic Methodologies
I. Introduction
A. Strategies for Combinatorial Library Syntheses
II. Solid-Phase Synthesis Methodologies
A. Introduction to Polymer-Supported Synthesis
1. Pros and Cons of Synthesis on Support
B. Synthetic Transformations on Solid Supports
1. Carbon-Heteroatom Coupling Reactions on Solid Supports
2. Carbon-Carbon Bond-Forming Reactions on Solid Supports
3. Transition Metal-Mediated Coupling Reactions
4. Intramolecular Cyclization-Resin-Cleavage Strategies
5. Cycloadditions
6. Multiple-Component Reactions on Solid Supports
C. Resin-to-Resin Transfer Reactions
III. Complex Multistep Synthesis on Solid Supports
A. Oligiomers—Natural and Unnatural
1. Peptide Synthesis on Solid Support
2. Oligonucleotide Synthesis on Solid Support
3. Oligosaccharide Synthesis on Solid Support
4. Unnatural Oligomers
B. Heterocycle/Pharmacophore Synthesis
C. Natural Product Total Syntheses on Solid Support
IV. Solution-Phase Synthesis Methodologies
A. Solution-Phase Polymer-Supported Synthesis
B. Solution-Phase Reactions Involving Scavenging Resins
C. Solution-Phase Reactions Involving Resin-Bound Reagents
D. Multistep Synthesis with Resin-Bound Scavengers and Reagents
V. Conclusion
References
18 Supports for Solid-Phase Synthesis
I. Resin Beads
A. Polystyrene Gel-Based Resins
B. Macroporous Resins
C. Poly(ethylene glycol)-Containing Resins
1. PS-PEG Supports
2. CLEAR Resins
3. Tetraethylene Glycol Diacrylate Cross-linked Polystyrene Support (TTEGDA-PS)
4. PEGA (Polyethylene glycol-poly-(N,N-dimethylacrylamide) Copolymer
5. Enhancing Bead Loading: Dendrimers as Powerful Enhances of Functionality
II. Synthesis On Surfaces
A. Pins and Crowns
B. Sheets
C. Glass
References
19 The NMR “Toolkit” for Compound Characterization
I. Introduction
II. Basic NMR Tools
A. 1D, 2D, 3D, and nD NMR
B. High-Field NMR
C. Broadband Decoupling
D. Spin Locks
E. Shaped Pulses
F. Indirect Detection
G. Pulsed-Field Gradients
1. PFG Variations of Existing Experiments
2. New Experiments Made Possible by PFG
III. Specialized NMR Tools
A. Biomolecular Structure Elucidation
1. Multiple RF-Channel NMR
2. Newer Biomolecular Experiments: TROSY, Hydrogen-Bond J Couplings, and Dipolar Couplings
B. Water (Solvent) Suppression
C. Hardware Developments
1. Probe Developments
2. Probes for Larger and Smaller Volume Samples
D. NMR of Solid-Phase Synthesis Resins
1. The Observed Nucleus
2. Choice of Resin and Solvent
3. Choice of NMR Probe
E. Flow NMR
1. LC-NMR
2. Flow Injection Analysis NMR (FIA-NMR) and Direct-Injection NMR (DI-NMR)
3. DI-NMR: Data Processing and Analysis
4. Other Techniques, Applications, and Hardware: SAR-by-NMR
F. Mixture Analysis: Diffusion-Ordered and Relaxation-Ordered Experiments
G. Other Probes: Superconducting Probes, Supercooled Probes, and Microcoils
H. Combination Experiments
I. Software
J. Quantification
K. Automation
L. Research NMR vs. Analytical NMR
IV. Conclusion
References
20 Materials Management
I. Introduction
II. Materials Management: A Definition
III. Role Of Materials Management in Drug Discovery
IV. Job Functions Involved In Materials Management
V. Materials Management Work Processes
A. Reagent Sourcing
B. Reagent Receiving and Tracking
C. New Compound Registration and Sample Submission
D. Master Plate Preparation and Distribution for High-Throughput Screening
E. Follow-up Screening
VI. Materials Management Technologies
A. Chemical Structure-Based Reagent Selection Tools and Products
B. ERP Systems, Supplier Catalogs, and Electronic Commerce
C. Robotic Weighing and Liquid Handling Workstations
D. Materials Management Systems
E. Automated Sample Storage and Retrieval Systems
VII. Future Directions

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Tags: Houng Yau Mei, Anthony W Czarnik, Drug Discovery