High-Throughput Mass Spectrometry in Drug Discovery

Cover
Title Page
Copyright Page
Contents
List of Contributors
Preface
List of Abbreviations
Section 1 Introduction
Chapter 1 Forty-Year Evolution of High-Throughput Mass Spectrometry: A Perspective
1.1 Introduction
1.2 Ionization Foundations of High-Throughput Mass Spectrometry
1.2.1 Historical Context of the Development of LC/MS. Ionization in Vacuum or at Atmospheric Pressure?
1.2.2 Ambient Sample Introduction Methods (Ambient Ionization) into an API Ion Source Without LC and Their HT-MS Potential
1.2.3 Direct and Indirect Affinity Measurements with ESI/MS for HTS
1.3 High-Speed Serial Chromatographic Sample Introduction
1.3.1 High Flow Rate Ion Sources
1.3.2 Fast Serial Scheduled, Staggered Chromatographic Separations with Fast Autosamplers
1.3.3 High-Speed Column Stationary Phases
1.4 Parallel Chromatographic Sample Introduction
1.4.1 Overview of Multichannel Indexed Ion Sources
1.4.2 Fluid Indexing
1.4.3 Spray Aerosol Indexing
1.4.4 Ion Beam Indexing
1.4.5 Ionization Indexing
1.4.6 Multichannel Autosampler and Pumps
1.5 High Repetition Rate Lasers
1.6 Ion Mobility for High-Speed Gas-Phase Separations
1.6.1 Motivation and Commercial Options
1.6.2 Origins of DMS
1.6.3 Chemically Based Selectivity with DMS to Mimic Chromatography
1.7 Mass Spectrometer Sensitivity
1.7.1 Historical Gains and Motivation for Sensitivity Improvements
1.8 High-Speed Sub-Microliter Volume Sampling
1.8.1 Small Sample Size and Low Volume Dispensing HT-MS Technologies
1.8.2 Shoot N Dilute Nanoliter Droplets
1.9 Conclusions and Future Prospects
References
Section 2 LC-MS
Chapter 2 The LeadSampler (LS-1) Sample Delivery System: Integrated Design and Features for High-Efficiency Bioanalysis
2.1 Introduction
2.2 Hardware and System Design
2.3 Software Integration
2.4 Enabling Emerging Techniques
2.5 Concluding Remarks
References
Chapter 3 Evolution of Multiplexing Technology for High-Throughput LC/MS Analyses
3.1 Introduction and Historical Developments
3.2 Developments Toward Fully Integrated Multiplexing Systems
3.3 Broadening Customer Options
3.4 Workflow and End-User Considerations
3.5 Conclusion
References
Section 3 ESI-MS Without Chromatographic Separation
Chapter 4 Direct Online SPE-MS for High-Throughput Analysis in Drug Discovery
4.1 Introduction
4.2 History of the Development of Direct Online SPE-MS
4.3 Hardware Details and Data Processing
4.4 Instrument Performance Highlights
4.5 Applications
4.6 Others
4.7 Future Perspectives
References
Chapter 5 Acoustic Sampling for Mass Spectrometry: Fundamentals and Applications in High-Throughput Drug Discovery
5.1 Introduction
5.2 Technology Overview
5.2.1 AMI-MS
5.2.2 ADE-OPI-MS
5.3 System Performance
5.3.1 AMI-MS Performance
5.3.2 ADE-OPI-MS Performance
5.4 Applications
5.4.1 High-Throughput Screening
5.4.2 High-Throughput ADME
5.4.3 In Situ Reaction Kinetics Monitoring
5.4.4 Bioanalysis
5.4.5 Compound QC
5.4.6 Parallel Medicinal Chemistry
5.4.7 High-Content Screening
5.5 Challenges and Limitations
5.6 Conclusion
References
Chapter 6 Ion Mobility Spectrometry-Mass Spectrometry for High-Throughput Analysis
6.1 Introduction of Ion Mobility Spectrometry
6.2 IMS Fundamental and Experiment
6.2.1 Ion Mobility Theory
6.2.2 Collision Cross Section Measurement
6.2.3 A Typical IMS Experiment
6.3 IMS Analysis and Applications
6.3.1 Separation of Isomeric and Isobaric Species by IMS
6.3.2 High-Throughput IMS Measurements and Building a CCS Library
6.3.3 LC-IMS-MS Analysis
6.3.4 High-Throughput Analysis Using Rapidfire SPE-IMS-MS
6.3.5 Software Tools for IMS Data Analysis
6.4 High-Resolution SLIM-IMS Developments
6.5 Conclusions
References
Chapter 7 Differential Mobility Spectrometry and Its Application to High-Throughput Analysis
7.1 Introduction
7.2 Separation Speed
7.2.1 Classical Low Field Ion Mobility
7.2.2 Differential Mobility Spectrometry
7.3 Separation Selectivity
7.3.1 Classical Low Field Ion Mobility
7.3.2 Differential Mobility Spectrometry
7.4 Ultrahigh-Throughput System with DMS
7.4.1 AEMS Data
7.4.2 DMS Sensitivity (Ion Transmission)
7.4.3 Examples of AEMS Analyses with DMS
7.4.4 DMS Tuning as a Component of the High-Throughput Workflow
7.4.5 Automation of the Tuning Process
7.5 Conclusions
7.A Chemical Structures
References
Section 4 Special Sample Arrangement
Chapter 8 Off-Line Affinity Selection Mass Spectrometry and Its Application in Lead Discovery
8.1 Introduction to Off-Line Affinity Selection Mass Spectrometry
8.2 Selected Off-Line Affinity Selection Technologies and Its Application in Lead Discovery
8.2.1 Membrane Ultrafiltration-Based Affinity Selection
8.2.2 Plate-Based Size Exclusion Chromatography
8.2.3 Bead-Based Affinity Selection
8.2.4 Self-Assembled Monolayers and Matrix-Assisted Laser Desorption Ionization (SAMDI)
8.2.5 Ultracentrifugation Affinity Selection
8.3 Future Perspectives
References
Chapter 9 Online Affinity Selection Mass Spectrometry
9.1 Introduction of Online Affinity Selection-Mass Spectrometry
9.2 Online ASMS Fundamental
9.3 Instrument Hardware and Software Consideration
9.3.1 SEC Selection, Fast Separation, and Temperature
9.3.2 MS: Low Resolution and High Resolution
9.3.3 Software: Key Features, False Positives, and False Negatives
9.3.4 Compound Libraries and Compression Level
9.4 Type of Assays Using ASMS
9.4.1 Target Identification and Validation
9.4.2 Hits ID from Combinatorial Libraries or Compound Collections
9.4.3 Hits Characterization and Leads Optimization
9.5 Applications Examples and New Modalities of ASMS for Drug Discovery
9.6 Future Perspectives
References
Chapter 10 Native Mass Spectrometry in Drug Discovery and Development
10.1 Introduction
10.1.1 The Significance of Non-Covalent Protein Complexes in Biology
10.1.2 Advantages and Disadvantages of Conventional Structural Analytical Techniques
10.2 Fundamentals of Native MS
10.2.1 Principles of Native Electrospray Ionization
10.2.2 Specific Sample Preparation to Preserve Non-Covalent Interactions and Be Compatible with ESI-MS Analysis
10.3 Instrumentation
10.3.1 Nano-ESI and ESI
10.3.2 Inline Desalting and Separations Coupled to Native Mass Spectrometry
10.3.3 High-Throughput Native Mass Spectrometry
10.3.4 Mass Analyzers
10.3.5 Data Processing
10.4 Application Highlights
10.4.1 Using Native MS to Develop Stable Protein Formulations
10.4.2 Native MS to Understand Drug/Target Interaction
10.4.3 Native Mass Spectrometry and Tractable Protein–Protein Interactions for Drug Discovery
10.4.4 Structural Stability Using Collision-Induced Unfolding
10.4.5 Vaccines and Virus Proteins Using CDMS
10.5 Conclusions and Future Directions
References
Section 5 Other Ambient Ionization Other than ESI
Chapter 11 Laser Diode Thermal Desorption-Mass Spectrometry (LDTD-MS): Fundamentals and Applications of Sub-Second Analysis in Drug Discovery Environment
11.1 A Historical Perspective of the LDTD
11.2 Instrumentation
11.2.1 LDTD Process
11.2.2 Sample Holder Design
11.2.3 Vapor Extraction Nozzle
11.3 Theoretical Background
11.3.1 Thermal Process
11.3.2 Gas Dynamics
11.3.3 Ionization
11.4 Sample Preparation
11.4.1 Motivations
11.4.2 General Guidelines
11.5 Applications
11.5.1 CYP Inhibition Analysis
11.5.2 Permeability
11.5.3 Protein Binding
11.5.4 Pharmacokinetic
11.5.5 Preparation Tips
11.6 Conclusion
11.6.1 Use and Merits of the Technology
11.6.2 Limitations
11.6.3 Perspectives
References
Chapter 12 Accelerating Drug Discovery with Ultrahigh-Throughput MALDI-TOF MS
12.1 Introduction
12.2 uHT-MALDI MS of Assays and Chemical Reactions
12.2.1 HT-MALDI of Enzymatic Assays
12.2.2 Screening Chemical Reactions Using uHT-MALDI
12.2.3 uHT-MALDI of Cell-Based Assays
12.2.4 uHT-MALDI of Other Types of Assays and Libraries
12.3 Bead-Based Workflows
12.4 Using Functionalized, Modified, and Microarrayed MALDI Plates for HT-MALDI
12.5 Summary and Future Trends
Acknowledgment
References
Chapter 13 Development and Applications of DESI-MSin Drug Discovery
13.1 Introduction
13.2 Development of DESI and Related Ambient Ionization Methods
13.3 Applications in Drug Discovery
13.3.1 Pharmaceutical Analysis and Therapeutic Drug Monitoring
13.3.2 Analysis of Drugs in Natural Products
13.3.3 DESI-Based Mass Spectrometry Imaging
13.3.4 Detection of Drug–Protein Interactions
13.3.5 High-Throughput Experimentation
13.3.6 High-Throughput Screening
13.4 Conclusions and Future Outlook
References
Section 6 Conclusion
Chapter 14 The Impact of HT-MS to Date and Its Potential to Shape the Future of Metrics-Based Experimentation and Analysis
14.1 Defining High-Throughput Mass Spectrometry (HT-MS)
14.2 HT-MS: Impact to Date
14.3 Considering How HT-MS Will Shape the Future of Drug Discovery
References
Index
EULA