Mass spectrometry in medicinal chemistry:
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| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Weinheim
WILEY-VCH
2007
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| Series: | Methods and principles in medicinal chemistry
36 |
| Subjects: | |
| Online Access: | Inhaltstext Inhaltsverzeichnis |
| Physical Description: | XXI, 437 S. Ill., graph. Darst. |
| ISBN: | 9783527314560 3527314563 |
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| 245 | 1 | 0 | |a Mass spectrometry in medicinal chemistry |c ed. by Klaus T. Wanner ... |
| 264 | 1 | |a Weinheim |b WILEY-VCH |c 2007 | |
| 300 | |a XXI, 437 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 1 | |a Methods and principles in medicinal chemistry |v 36 | |
| 650 | 4 | |a Chemistry, Pharmaceutical |x methods | |
| 650 | 4 | |a Drug Design | |
| 650 | 4 | |a Drug development | |
| 650 | 4 | |a Mass Spectrometry |x methods | |
| 650 | 4 | |a Mass spectrometry | |
| 650 | 4 | |a Pharmaceutical Preparations |x analysis | |
| 650 | 4 | |a Pharmaceutical chemistry | |
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Contents
Preface XV
A Personal Foreword XVII
List of Contributors XIX
I Introduction to MS in bioanalysis 1
1 Mass Spectrometry in Bioanalysis Methods, Principles and
Instrumentation 3
Gerard Hopfgartner
1.1 Introduction 3
1.2 Fundamentals 4
1.3 Ionization Techniques 10
1.3.1 Electron Impact and Chemical Ionization 10
1.3.2 Atmospheric Pressure Ionization 12
1.3.2.1 Electrospray 14
1.3.2.2 Atmospheric Pressure Chemical Ionization 17
1.3.2.3 Photoionization 19
1.3.2.4 Multiple Ionization Source 19
1.3.2.5 Desorption Electrospray and Direct Analysis in Real Time 20
1.3.3 Matrix Assisted Laser Desorption Ionization 21
1.4 Mass Analyzers 23
1.4.1 Quadrupole Analyzers 23
1.4.2 Triple Quadrupole Mass Analyzer 24
1.4.3 Ion Trap Mass Spectrometry 27
1.4.4 Triple Quadrupole Linear Ion Trap 30
1.4.5 Time of Flight Mass Spectrometry 33
1.4.6 Fourier Transform Mass Spectrometry 36
1.4.6.1 Fourier Transform Ion Cyclotron Resonance Mass Spectrometry 36
1.4.6.2 Orbitrap Mass Spectrometer 37
1.5 Ion Detectors 38
1.6 Practical Aspects and Applications in Bioanalysis 41
Mass Spectrometry in Medicinal Chemistry. Edited by K. T. Wanner and G. Hofher
Copyright © 2007 WILEY VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 978 3 527 31456 0
VI I Contents
1.6.1 Introduction 41
1.6.2 Quantitative Analysis in Biological Matrices 42
1.6.3 Drug Metabolism 45
1.6.4 Analysis of Proteins 49
1.7 Perspectives 54
1.8 Common Definitions and Abbreviations 58
References 58
II Studying target ligand interactions analyzing the ligand by MS 63
2 Drug Screening Using Cel Permeation Chromatography Spin Columns
Coupled with ESI MS 65
Marshall M. Siegel
2.1 Introduction 65
2.1.1 Preface 65
2.1.2 Direct and Indirect ESI MS Analysis of Non covalent Drug Protein
Complexes 65
2.1.3 Advantages of GPC Spin Columns 66
2.1.4 Application of Equilibrium and Non equilibrium Theory for the
Analysis of GPC Spin Column Eluates 68
2.1.4.1 Sample Prepared Under Equilibrium Conditions Prior to Spin Column
Treatment 69
2.1.4.2 Calculation for Predicting the Concentration of Sample Complex Eluted
From the Spin Column 69
2.1.4.3 Estimation of Relative Binding Affinities from GPC Spin Column/
ESI MS Data 72
2.1.4.4 Experimental Determination of the Ka Value from GPC Spin Column/
ESI MS Data 72
2.2 Experimental 73
2.2.1 Spin Columns 73
2.2.2 Spin Column Media: Advantages and Disadvantages, Volatile vs Non¬
volatile Buffers 74
2.2.3 Preparing Non covalent Complexes in Protein Buffer; Protein
Concentration, Ligand Concentration, Incubation Time 75
2.2.4 Sample Organization: Single Samples vs Mixtures, Mixture Set up:
Compatibility of Components, Plate Set up 79
2.2.5 Pooling Spin Column Eluates for Higher Throughput 80
2.2.6 Manual vs Robotic Instrumentation for Sample Preparation and
Acquiring Spin Column Eluates 80
2.2.7 ESI Mass Spectrometer: ESI, APCI, Photodissociation, Positive/
Negative Ionization 81
2.2.8 ESI Multi sprayer (MUX) Technology; Sample Throughput; Protein
Consumption 82
2.2.9 Reversed Phase (RP) HPLC ESI MS Considerations 83
2.2.10 Protein Removal for Optimum Sensitivity 84
Contents I VII
2.2.11 Data Reduction and Automated Interpretation of GPC Spin Column/
ESI MS Data 84
2.3 Results 89
2.3.1 Secondary Screens 89
2.3.1.1 GPC Spin Column/ESI MS Drug Screening Demonstration
Papers 89
2.3.1.2 Estrogen Receptor Target 89
2.3.1.3 Non covalent Binding of Drugs to RNA/DNA Targets 90
2.3.1.4 Amgen Secondary Screens 94
2.3.1.5 Novartis Secondary Screens 94
2.3.2 Primary Screens 94
2.3.2.1 RGS4 Protein Target 94
2.3.2.2 Amgen Primary Screens 98
2.3.2.3 Novartis Primary Screens 98
2.3.3 Additional Spin Column Methods 99
2.3.3.1 Competition Experiments of Inhibitor Mixture with Protein Target 99
2.3.3.2 GPC Spin Column/ESI MS Determination of Binding Sites 101
2.3.3.3 Obtaining MS EC50S and Kjs for Ligands Non covalently Bound to
Protein Active Sites 112
2.3.3.4 Multiple Passes Through Spin Columns Finding Strongest
Binders 113
2.3.3.5 Reverse Screening with GPC Spin Columns 113
2.4 Conclusions 113
2.4.1 GPC Spin Column/ESI MS: Ease of Use, Mixture Analysis, High
Speed, Reliability, Uncoupling of GPC from ESI MS and HPLC
ESI MS 113
2.4.2 Comparison of GPC Spin Column/HPLC ESI MS with Tandem
Chromatographic Method of GPC/HPLC ESI MS 114
2.4.3 Future Developments 115
2.4.3.1 MS and HPLC Improvements 115
2.4.3.2 Use of Automated Nanospray for Greater Sensitivity and Smaller
Sample Size (Less Protein/Drug) 115
2.4.3.3 Microfluidic Systems: Sensitivity, High Speed 126
2.4.3.4 GPC Spin Column Eluates Analyzed by ESI/Ion Mobility/Mass
Spectrometry 116
2.4.3.5 GPC Spin Columns with Matrixless MALDI MS and Gyros GPC
Microfluidic ESI/MALDI MS System 116
References 117
3 ALIS: An Affinity Selection Mass Spectrometry System for the Discovery and
Characterization of Protein Ligand Interactions 121
Allen Annis, Cheng Chi Chuang, and Nairn Nazef
3.1 Introduction 121
3.1.1 State of the Art 122
VIIII Contents
3.1.1.1 Spectroscopic and Biophysical Methods 122
3.1.1.2 Mass Spectrometry based Methods 123
3.2 ALIS: An Affinity Selection Mass Spectrometry System based on
Continuous SEC 124
3.2.1 ALIS System Design 126
3.3 Discovery of Ligands from Combinatorial Libraries 127
3.4 Quantitative Binding Affinity Measurement 130
3.4.1 Theory 131
3.4.2 Simulations and Experimental Results 134
3.5 Competition based Binding Site Determination and Affinity Ranking in
Mixtures 135
3.5.1 Binding Site Classification 136
3.5.2 Affinity Ranking in Compound Mixtures 140
3.6 Protein Ligand Dissociation Rate Measurement 142
3.6.1 Theory 143
3.6.2 Simulations 145
3.6.3 Experimental Results 147
3.7 Conclusions 150
3.8 Future Directions 151
References 152
4 Library Screening Using Ultrafiltration and Mass Spectrometry 157
Timothy E. Cloutier and Kenneth M. Comess
4.1 Introduction 157
4.2 Ultra high Throughput Filtration based Affinity Screening as a
Discovery Tool 163
4.2.1 Affinity Selection/Mass Spectrometry 163
4.2.2 Primary Screening Strategy 164
4.2.3 Retesting and Deconvolution Strategy 167
4.2.4 Promiscuous Compound Filter 168
4.2.5 MurF Lead Discovery 171
4.3 Additional Affinity Screening Methodology That Includes Mass
Spectrometry based Readout 177
4.3.1 Pulsed Ultrafiltration MS 177
4.4 Conclusions and Future Directions 180
References 181
5 Continuous flow Systems for Ligand Binding and Enzyme Inhibition Assays
Based on Mass Spectrometry 185
Hubertus Irth
5.1 Introduction 185
5.2 Continuous flow Enzyme Assays Based on Mass Spectrometry 386
Contents IIX
5.2.1 Assay Principle 186
5.2.2 ESI MS Assay of Cathepsin B 188
5.2.2.1 MS Assay Development for Cathepsin B 188
5.2.2.2 Compatibility of Cathepsin B Assay with MS Detection 188
5.2.2.3 On line Coupling of MS based Cathepsin B Assay to HPLC 190
5.2.2.4 Screening of Natural Products for Cathepsin B Activity 192
5.2.3 ESI MS Assay of Acetylcholinesterase 194
5.2.3.1 MS Assay Development for Acetylcholinesterase 194
5.2.3.2 Assay Validation and Stability 197
5.2.3.3 Screening of Natural Products for Acetylcholinesterase Activity 197
5.2.4 Miniaturization of Electrospray MS Assays 198
5.2.4.1 Chip based Electrospray MS Assays 198
5.2.4.2 Chip Performance 199
5.2.4.3 Sensitivity of the Chip based MS Screening System 200
5.3 Continuous flow Ligand Binding Assays Based on Mass
Spectromerry 200
5.3.1 Assay Principle 200
5.3.2 Optimization of MS Conditions 201
5.3.3 On line Continuous flow Biochemical Interaction 202
5.3.4 Monitoring Bioactive Compounds 204
5.3.5 Antibody Antigen Interactions 205
5.3.6 Continuous flow Multi protein Binding Assays Using Electrospray
MS 205
5.4 MS Assay Based on Dissociation of Isolated Protein Ligand
Complexes 207
5.4.1 Assay Set up 207
5.4.2 Flow Injection Label free MS Assay 209
5.4.3 Flow Injection Label free MS Assay Screening of Natural Extracts 211
5.5 Future Prospects 211
References 213
6 Frontal Affinity Chromatography Mass Spectrometry for Ligand Discovery
and Characterization 217
Nora Chan, Darren Lewis, Michele Kelly, Ella S.M. Ng, and David C. Schriemer
6.1 Introduction 217
6.1.1 The Basic Frontal Method 218
6.1.2 FAC Basic Theory 220
6.1.3 FAC Advantages 221
6.1.4 FAC Disadvantages 223
6.2 Enabling FAC with MS Detection 224
6.2.1 Direct FAC MS Methods for Compound Binding Data 224
6.2.2 Direct Method for Discovering and Ranking Multiple Ligands 226
6.2.3 Indirect Methods 232
X I Contents
6.3 System Advancements Fluidics, Immobilization, Detection 235
6.3.1 Column 235
6.3.2 System 239
6.3.3 Breakthrough Curve Detection and Data Analysis 241
6.4 Select Applications 242
6.5 Summary and Evaluation 243
References 244
7 MS Binding Assays An Alternative to Radioligand Binding 247
Ceorg Hofner, Christine Zepperitz, and Klaus T. Wanner
7.1 Introduction 247
7.2 Radioligand Binding Assays 248
7.2.1 General Principle 248
7.2.1.1 Saturation Assays 248
7.2.1.2 Competition Assays 249
7.2.1.3 Kinetic Assays 250
7.2.2 Application 251
7.2.3 Disadvantages and Alternatives 252
7.3 MS Binding Assays 254
7.3.1 MS Binding Assays Quantifying the Nonbound Marker 255
7.3.1.1 Competition Assays for Di and D2 Dopamine Receptors 257
7.3.1.2 Library Screening and Competition Assays for ,u Opioid Receptors 263
7.3.2 MS Binding Assays Quantifying the Bound Marker 267
7.3.2.1 Saturation Assays for mGATl 268
7.3.2.2 Competition Assays for mGATl 272
7.3.2.3 Kinetic Assays for mGATl 272
7.4 Summary and Perspectives 276
References 278
8 Laser Desorption Assays MALDI MS, DIOS MS, and SAMDI MS 285
Martin Vogel, Andy Schejfer, Andre Liesener, and Uwe Karst
8.1 MALDI MS Assays 285
8.1.1 Principles of MALDI 285
8.1.2 Application of MALDI MS in Bioanalysis 287
8.2 DIOS: Desorption/Ionization on Silicon 289
8.2.1 Principles of DIOS 289
8.2.2 Application of DIOS in Bioanalysis 292
8.3 SAMDI: Self assembled Monolayers for MALDI MS 295
8.3.1 Principles of SAMDI MS 295
8.3.2 Application of SAMDI in Bioanalysis 297
8.4 Conclusion 299
References 300
Contents I XI
III Studying target ligand interactions analyzing intact target ligand complexes
by MS 303
9 Tethering: Fragment based Drug Discovery by Mass Spectrometry 305
Mark T. Concilia and Daniel A Erlanson
9.1 Introduction 305
9.2 Reduction to Practice 307
9.2.1 Technique 307
9.2.2 Advantages 310
9.3 Finding Fragments: Thymidylate Synthase Proof of Principle 310
9.4 Finding and Linking Fragments in One Step: Tethering with
Extenders 312
9.4.1 Caspase 3 312
9.4.2 Caspase 1 316
9.5 Conclusions 316
References 318
10 Interrogation of Noncovalent Complexes by ESI MS: A Powerful Platform
for High Throughput Drug Discovery 321
Steven A Hofstadler and Kristin A Sannes Lowery
10.1 Analysis of Noncovalent Complexes by ESI MS 321
10.1.1 Solution Conditions 321
10.1.2 Proteins 322
10.1.3 Oligonucleotides 323
10.2 Multitarget Affinity/Specificity Screening 328
10.3 Multitarget Affinity/Specificity Screening in a High Throughput
Format 329
10.4 Affinity/Specificity 330
10.5 SAR by MS 332
10.6 Future Directions 333
References 335
IV Studying target ligand interactions analyzing the target binding site by
MS 339
11 Quantification of Protein Ligand Interactions in Solution by Hydrogen/
Deuterium Exchange (PLIMSTEX) 341
Mei M. Zhu, David Hambly, and Michael L Gross
11.1 Introduction 341
11.2 The PLIMSTEX Method 342
11.2.1 A General Protocol of H/D Exchange and LC/MS Analysis for
PLIMSTEX 342
XIII Contents
11.2.2 Determination and Interpretation of the Titration Curves 343
11.3 Applications of PLIMSTEX 345
11.3.1 Determination of Association Constant (Ka), Stoichiometry (n), and
Protection (ADf) 345
11.3.2 Ras GDP Interacting with Mg2+: A 1:1 ProteinrMetal Ion
Interaction 347
11.3.2.1 Kinetic Study of Forward H/D Exchange Ras GDP with Different
[Mg2+] 347
11.3.2.2 PLIMSTEX Results for Ras GDP Titrated with Mg2+ 348
11.3.2.3 Interpretation of PLIMSTEX Results with H/D Exchange Kinetics
349
11.3.2.4 Application of PLIMSTEX to Relatively Weak Protein Ligand
Binding 350
11.3.2.5 Experimental Issues Regarding Using Metal Chelators 350
11.3.3 Apo CaM Interacting with Ca2+: A 1:4 Protein:Metal Ion
Interaction 351
11.3.3.1 PLIMSTEX Results for CaM and Intermediate Protein Ligand Binding
Species 351
11.3.3.2 PLIMSTEX in Biologically Relevant Media and High Ionic
Strength 352
11.3.4 Apo IFABP and Oleate: A Protein Small Organic Molecule
Interaction 353
11.3.5 Holo CaM and Melittin: A Protein Peptide Interaction 354
11.3.5.1 PLIMSTEX Curves Under Different Holo CaM Concentrations 355
11.3.6 Self association of Insulin: A Protein Protein Interaction 356
11.3.6.1 Modified Version of PLIMSTEX for Insulin Self association 356
11.4 Features of PLIMSTEX 357
11.4.1 Determines Kt, Stoichiometry, and Protection (AD;) 357
11.4.2 Requires Low Quantities of Protein 357
11.4.3 Relies Only on MS to Measure m/z And Not Solution
Concentration 358
11.4.4 Works in Biologically Relevant Media at High Ionic Strength 359
11.4.5 Does Not Need Specially Labeled Protein or Iigand 359
11.4.6 Avoids Perturbation of the Binding Equilibrium 360
11.4.7 Has Potential for Peptide Resolution 360
11.4.8 Current Challenges and Future Directions 360
11.5 Fast Radical Footprinting for Protein Ligand Interaction
Analysis 361
11.5.1 Rationale for Hydroxyl Radicals as a Probe 362
11.5.2 Methods for Generating Hydroxyl Radicals 362
11.5.3 Fast Photochemical Oxidation of Proteins 363
11.5.4 Locating the Sites of Oxidation 364
11.5.5 Application of FPOP to Apomyoglobin 364
11.5.6 Advantages of FPOP 366
Contents I XIII
11.6 Potential Applications in Drug Discovery 367
References 368
12 Protein targeting Drug Discovery Guided by Hydrogen/Deuterium Exchange
Mass Spectrometry (DXMS) 377
Yoshitomo Hamuro, Stephen J. Coales, and Virgil L Woods Jr
12.1 Introduction 377
12.2 Theory of H/D Exchange 378
12.2.1 Amide H/D Exchange 378
12.2.2 Protection Factor 378
12.2.3 Backbone Amide Hydrogens as Thermodynamic Sensors 379
12.3 Overview of H/D Exchange Technologies 380
12.3.1 On Exchange Reaction 380
12.3.2 Quench of Exchange Reaction 380
12.3.3 Protein Fragmentation by Proteolysis 381
12.3.4 Digestion Optimization 381
12.3.5 HPLC Separation 381
12.3.6 Mass Analysis 381
12.37 Automation of H/D Exchange by MS 382
12.3.8 Automated Data Analysis 383
12.4 DXMS guided Design of Well Crystallizing Proteins 383
12.4.1 Disordered Regions and Protein Crystallography 383
12.4.2 Poorly Crystallizing Proteins Contain Substantial Disordered
Regions 384
12.4.3 Disorder depleted Mutant Preserved Ordered Structure 384
12.4.4 Disorder depleted Mutant Improved Crystallization Efficiency and
Produced High Resolution Structure 384
12.5 Rapid Characterization of Protein Conformational Change with
DXMS 385
12.5.1 Human Growth Hormone 386
12.5.2 H/D Exchange of hGH 386
12.5.3 Free Energy Change upon Folding of hGH 386
12.6 Application of H/D Exchange to Protein Small Molecule Ligand
Interactions 388
12.6.1 p38 Mitogen activated Protein Kinase 388
12.6.2 H/D Exchange of p38 MAP Kinase 389
12.6.3 Peroxisome Proliferator activated Receptor y 390
12.6.4 H/D Exchange of PPARy 390
12.7 DXMS guided Design of Small Molecules that Target Protein Protein
Interaction Surfaces 391
12.8 Optimal Formulation and Quality Control of Whole protein
Therapeutics with DXMS 393
12.9 Conclusions 394
References 394
XIV I Contents
V MS in early pharmacokinetics 399
13 Mass Spectrometry in Early Pharmacokinetic Investigations 401
Walter A. Korfmacher
13.1 Introduction 401
13.2 HPLC MS/MS Overview 402
13.3 In Vitro Applications 405
13.4 In Vivo Applications 406
13.5 Rapid Method Development 408
13.6 Increasing Throughput in HPLC MS/MS 410
13.7 Matrix Effects 411
13.8 Discovery PK Assay Rules 413
13.9 New Technology in LC MS 415
13.10 Conclusion 419
References 419
Index 429 |
| adam_txt |
Contents
Preface XV
A Personal Foreword XVII
List of Contributors XIX
I Introduction to MS in bioanalysis 1
1 Mass Spectrometry in Bioanalysis Methods, Principles and
Instrumentation 3
Gerard Hopfgartner
1.1 Introduction 3
1.2 Fundamentals 4
1.3 Ionization Techniques 10
1.3.1 Electron Impact and Chemical Ionization 10
1.3.2 Atmospheric Pressure Ionization 12
1.3.2.1 Electrospray 14
1.3.2.2 Atmospheric Pressure Chemical Ionization 17
1.3.2.3 Photoionization 19
1.3.2.4 Multiple Ionization Source 19
1.3.2.5 Desorption Electrospray and Direct Analysis in Real Time 20
1.3.3 Matrix Assisted Laser Desorption Ionization 21
1.4 Mass Analyzers 23
1.4.1 Quadrupole Analyzers 23
1.4.2 Triple Quadrupole Mass Analyzer 24
1.4.3 Ion Trap Mass Spectrometry 27
1.4.4 Triple Quadrupole Linear Ion Trap 30
1.4.5 Time of Flight Mass Spectrometry 33
1.4.6 Fourier Transform Mass Spectrometry 36
1.4.6.1 Fourier Transform Ion Cyclotron Resonance Mass Spectrometry 36
1.4.6.2 Orbitrap Mass Spectrometer 37
1.5 Ion Detectors 38
1.6 Practical Aspects and Applications in Bioanalysis 41
Mass Spectrometry in Medicinal Chemistry. Edited by K. T. Wanner and G. Hofher
Copyright © 2007 WILEY VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 978 3 527 31456 0
VI I Contents
1.6.1 Introduction 41
1.6.2 Quantitative Analysis in Biological Matrices 42
1.6.3 Drug Metabolism 45
1.6.4 Analysis of Proteins 49
1.7 Perspectives 54
1.8 Common Definitions and Abbreviations 58
References 58
II Studying target ligand interactions analyzing the ligand by MS 63
2 Drug Screening Using Cel Permeation Chromatography Spin Columns
Coupled with ESI MS 65
Marshall M. Siegel
2.1 Introduction 65
2.1.1 Preface 65
2.1.2 Direct and Indirect ESI MS Analysis of Non covalent Drug Protein
Complexes 65
2.1.3 Advantages of GPC Spin Columns 66
2.1.4 Application of Equilibrium and Non equilibrium Theory for the
Analysis of GPC Spin Column Eluates 68
2.1.4.1 Sample Prepared Under Equilibrium Conditions Prior to Spin Column
Treatment 69
2.1.4.2 Calculation for Predicting the Concentration of Sample Complex Eluted
From the Spin Column 69
2.1.4.3 Estimation of Relative Binding Affinities from GPC Spin Column/
ESI MS Data 72
2.1.4.4 Experimental Determination of the Ka Value from GPC Spin Column/
ESI MS Data 72
2.2 Experimental 73
2.2.1 Spin Columns 73
2.2.2 Spin Column Media: Advantages and Disadvantages, Volatile vs Non¬
volatile Buffers 74
2.2.3 Preparing Non covalent Complexes in Protein Buffer; Protein
Concentration, Ligand Concentration, Incubation Time 75
2.2.4 Sample Organization: Single Samples vs Mixtures, Mixture Set up:
Compatibility of Components, Plate Set up 79
2.2.5 Pooling Spin Column Eluates for Higher Throughput 80
2.2.6 Manual vs Robotic Instrumentation for Sample Preparation and
Acquiring Spin Column Eluates 80
2.2.7 ESI Mass Spectrometer: ESI, APCI, Photodissociation, Positive/
Negative Ionization 81
2.2.8 ESI Multi sprayer (MUX) Technology; Sample Throughput; Protein
Consumption 82
2.2.9 Reversed Phase (RP) HPLC ESI MS Considerations 83
2.2.10 Protein Removal for Optimum Sensitivity 84
Contents I VII
2.2.11 Data Reduction and Automated Interpretation of GPC Spin Column/
ESI MS Data 84
2.3 Results 89
2.3.1 Secondary Screens 89
2.3.1.1 GPC Spin Column/ESI MS Drug Screening Demonstration
Papers 89
2.3.1.2 Estrogen Receptor Target 89
2.3.1.3 Non covalent Binding of Drugs to RNA/DNA Targets 90
2.3.1.4 Amgen Secondary Screens 94
2.3.1.5 Novartis Secondary Screens 94
2.3.2 Primary Screens 94
2.3.2.1 RGS4 Protein Target 94
2.3.2.2 Amgen Primary Screens 98
2.3.2.3 Novartis Primary Screens 98
2.3.3 Additional Spin Column Methods 99
2.3.3.1 Competition Experiments of Inhibitor Mixture with Protein Target 99
2.3.3.2 GPC Spin Column/ESI MS Determination of Binding Sites 101
2.3.3.3 Obtaining MS EC50S and Kjs for Ligands Non covalently Bound to
Protein Active Sites 112
2.3.3.4 Multiple Passes Through Spin Columns Finding Strongest
Binders 113
2.3.3.5 Reverse Screening with GPC Spin Columns 113
2.4 Conclusions 113
2.4.1 GPC Spin Column/ESI MS: Ease of Use, Mixture Analysis, High
Speed, Reliability, Uncoupling of GPC from ESI MS and HPLC
ESI MS 113
2.4.2 Comparison of GPC Spin Column/HPLC ESI MS with Tandem
Chromatographic Method of GPC/HPLC ESI MS 114
2.4.3 Future Developments 115
2.4.3.1 MS and HPLC Improvements 115
2.4.3.2 Use of Automated Nanospray for Greater Sensitivity and Smaller
Sample Size (Less Protein/Drug) 115
2.4.3.3 Microfluidic Systems: Sensitivity, High Speed 126
2.4.3.4 GPC Spin Column Eluates Analyzed by ESI/Ion Mobility/Mass
Spectrometry 116
2.4.3.5 GPC Spin Columns with Matrixless MALDI MS and Gyros GPC
Microfluidic ESI/MALDI MS System 116
References 117
3 ALIS: An Affinity Selection Mass Spectrometry System for the Discovery and
Characterization of Protein Ligand Interactions 121
Allen Annis, Cheng Chi Chuang, and Nairn Nazef
3.1 Introduction 121
3.1.1 State of the Art 122
VIIII Contents
3.1.1.1 Spectroscopic and Biophysical Methods 122
3.1.1.2 Mass Spectrometry based Methods 123
3.2 ALIS: An Affinity Selection Mass Spectrometry System based on
Continuous SEC 124
3.2.1 ALIS System Design 126
3.3 Discovery of Ligands from Combinatorial Libraries 127
3.4 Quantitative Binding Affinity Measurement 130
3.4.1 Theory 131
3.4.2 Simulations and Experimental Results 134
3.5 Competition based Binding Site Determination and Affinity Ranking in
Mixtures 135
3.5.1 Binding Site Classification 136
3.5.2 Affinity Ranking in Compound Mixtures 140
3.6 Protein Ligand Dissociation Rate Measurement 142
3.6.1 Theory 143
3.6.2 Simulations 145
3.6.3 Experimental Results 147
3.7 Conclusions 150
3.8 Future Directions 151
References 152
4 Library Screening Using Ultrafiltration and Mass Spectrometry 157
Timothy E. Cloutier and Kenneth M. Comess
4.1 Introduction 157
4.2 Ultra high Throughput Filtration based Affinity Screening as a
Discovery Tool 163
4.2.1 Affinity Selection/Mass Spectrometry 163
4.2.2 Primary Screening Strategy 164
4.2.3 Retesting and Deconvolution Strategy 167
4.2.4 Promiscuous Compound Filter 168
4.2.5 MurF Lead Discovery 171
4.3 Additional Affinity Screening Methodology That Includes Mass
Spectrometry based Readout 177
4.3.1 Pulsed Ultrafiltration MS 177
4.4 Conclusions and Future Directions 180
References 181
5 Continuous flow Systems for Ligand Binding and Enzyme Inhibition Assays
Based on Mass Spectrometry 185
Hubertus Irth
5.1 Introduction 185
5.2 Continuous flow Enzyme Assays Based on Mass Spectrometry 386
Contents IIX
5.2.1 Assay Principle 186
5.2.2 ESI MS Assay of Cathepsin B 188
5.2.2.1 MS Assay Development for Cathepsin B 188
5.2.2.2 Compatibility of Cathepsin B Assay with MS Detection 188
5.2.2.3 On line Coupling of MS based Cathepsin B Assay to HPLC 190
5.2.2.4 Screening of Natural Products for Cathepsin B Activity 192
5.2.3 ESI MS Assay of Acetylcholinesterase 194
5.2.3.1 MS Assay Development for Acetylcholinesterase 194
5.2.3.2 Assay Validation and Stability 197
5.2.3.3 Screening of Natural Products for Acetylcholinesterase Activity 197
5.2.4 Miniaturization of Electrospray MS Assays 198
5.2.4.1 Chip based Electrospray MS Assays 198
5.2.4.2 Chip Performance 199
5.2.4.3 Sensitivity of the Chip based MS Screening System 200
5.3 Continuous flow Ligand Binding Assays Based on Mass
Spectromerry 200
5.3.1 Assay Principle 200
5.3.2 Optimization of MS Conditions 201
5.3.3 On line Continuous flow Biochemical Interaction 202
5.3.4 Monitoring Bioactive Compounds 204
5.3.5 Antibody Antigen Interactions 205
5.3.6 Continuous flow Multi protein Binding Assays Using Electrospray
MS 205
5.4 MS Assay Based on Dissociation of Isolated Protein Ligand
Complexes 207
5.4.1 Assay Set up 207
5.4.2 Flow Injection Label free MS Assay 209
5.4.3 Flow Injection Label free MS Assay Screening of Natural Extracts 211
5.5 Future Prospects 211
References 213
6 Frontal Affinity Chromatography Mass Spectrometry for Ligand Discovery
and Characterization 217
Nora Chan, Darren Lewis, Michele Kelly, Ella S.M. Ng, and David C. Schriemer
6.1 Introduction 217
6.1.1 The Basic Frontal Method 218
6.1.2 FAC Basic Theory 220
6.1.3 FAC Advantages 221
6.1.4 FAC Disadvantages 223
6.2 Enabling FAC with MS Detection 224
6.2.1 Direct FAC MS Methods for Compound Binding Data 224
6.2.2 Direct Method for Discovering and Ranking Multiple Ligands 226
6.2.3 Indirect Methods 232
X I Contents
6.3 System Advancements Fluidics, Immobilization, Detection 235
6.3.1 Column 235
6.3.2 System 239
6.3.3 Breakthrough Curve Detection and Data Analysis 241
6.4 Select Applications 242
6.5 Summary and Evaluation 243
References 244
7 MS Binding Assays An Alternative to Radioligand Binding 247
Ceorg Hofner, Christine Zepperitz, and Klaus T. Wanner
7.1 Introduction 247
7.2 Radioligand Binding Assays 248
7.2.1 General Principle 248
7.2.1.1 Saturation Assays 248
7.2.1.2 Competition Assays 249
7.2.1.3 Kinetic Assays 250
7.2.2 Application 251
7.2.3 Disadvantages and Alternatives 252
7.3 MS Binding Assays 254
7.3.1 MS Binding Assays Quantifying the Nonbound Marker 255
7.3.1.1 Competition Assays for Di and D2 Dopamine Receptors 257
7.3.1.2 Library Screening and Competition Assays for ,u Opioid Receptors 263
7.3.2 MS Binding Assays Quantifying the Bound Marker 267
7.3.2.1 Saturation Assays for mGATl 268
7.3.2.2 Competition Assays for mGATl 272
7.3.2.3 Kinetic Assays for mGATl 272
7.4 Summary and Perspectives 276
References 278
8 Laser Desorption Assays MALDI MS, DIOS MS, and SAMDI MS 285
Martin Vogel, Andy Schejfer, Andre Liesener, and Uwe Karst
8.1 MALDI MS Assays 285
8.1.1 Principles of MALDI 285
8.1.2 Application of MALDI MS in Bioanalysis 287
8.2 DIOS: Desorption/Ionization on Silicon 289
8.2.1 Principles of DIOS 289
8.2.2 Application of DIOS in Bioanalysis 292
8.3 SAMDI: Self assembled Monolayers for MALDI MS 295
8.3.1 Principles of SAMDI MS 295
8.3.2 Application of SAMDI in Bioanalysis 297
8.4 Conclusion 299
References 300
Contents I XI
III Studying target ligand interactions analyzing intact target ligand complexes
by MS 303
9 Tethering: Fragment based Drug Discovery by Mass Spectrometry 305
Mark T. Concilia and Daniel A Erlanson
9.1 Introduction 305
9.2 Reduction to Practice 307
9.2.1 Technique 307
9.2.2 Advantages 310
9.3 Finding Fragments: Thymidylate Synthase Proof of Principle 310
9.4 Finding and Linking Fragments in One Step: Tethering with
Extenders 312
9.4.1 Caspase 3 312
9.4.2 Caspase 1 316
9.5 Conclusions 316
References 318
10 Interrogation of Noncovalent Complexes by ESI MS: A Powerful Platform
for High Throughput Drug Discovery 321
Steven A Hofstadler and Kristin A Sannes Lowery
10.1 Analysis of Noncovalent Complexes by ESI MS 321
10.1.1 Solution Conditions 321
10.1.2 Proteins 322
10.1.3 Oligonucleotides 323
10.2 Multitarget Affinity/Specificity Screening 328
10.3 Multitarget Affinity/Specificity Screening in a High Throughput
Format 329
10.4 Affinity/Specificity 330
10.5 SAR by MS 332
10.6 Future Directions 333
References 335
IV Studying target ligand interactions analyzing the target binding site by
MS 339
11 Quantification of Protein Ligand Interactions in Solution by Hydrogen/
Deuterium Exchange (PLIMSTEX) 341
Mei M. Zhu, David Hambly, and Michael L Gross
11.1 Introduction 341
11.2 The PLIMSTEX Method 342
11.2.1 A General Protocol of H/D Exchange and LC/MS Analysis for
PLIMSTEX 342
XIII Contents
11.2.2 Determination and Interpretation of the Titration Curves 343
11.3 Applications of PLIMSTEX 345
11.3.1 Determination of Association Constant (Ka), Stoichiometry (n), and
Protection (ADf) 345
11.3.2 Ras GDP Interacting with Mg2+: A 1:1 ProteinrMetal Ion
Interaction 347
11.3.2.1 Kinetic Study of Forward H/D Exchange Ras GDP with Different
[Mg2+] 347
11.3.2.2 PLIMSTEX Results for Ras GDP Titrated with Mg2+ 348
11.3.2.3 Interpretation of PLIMSTEX Results with H/D Exchange Kinetics
349
11.3.2.4 Application of PLIMSTEX to Relatively Weak Protein Ligand
Binding 350
11.3.2.5 Experimental Issues Regarding Using Metal Chelators 350
11.3.3 Apo CaM Interacting with Ca2+: A 1:4 Protein:Metal Ion
Interaction 351
11.3.3.1 PLIMSTEX Results for CaM and Intermediate Protein Ligand Binding
Species 351
11.3.3.2 PLIMSTEX in Biologically Relevant Media and High Ionic
Strength 352
11.3.4 Apo IFABP and Oleate: A Protein Small Organic Molecule
Interaction 353
11.3.5 Holo CaM and Melittin: A Protein Peptide Interaction 354
11.3.5.1 PLIMSTEX Curves Under Different Holo CaM Concentrations 355
11.3.6 Self association of Insulin: A Protein Protein Interaction 356
11.3.6.1 Modified Version of PLIMSTEX for Insulin Self association 356
11.4 Features of PLIMSTEX 357
11.4.1 Determines Kt, Stoichiometry, and Protection (AD;) 357
11.4.2 Requires Low Quantities of Protein 357
11.4.3 Relies Only on MS to Measure m/z And Not Solution
Concentration 358
11.4.4 Works in Biologically Relevant Media at High Ionic Strength 359
11.4.5 Does Not Need Specially Labeled Protein or Iigand 359
11.4.6 Avoids Perturbation of the Binding Equilibrium 360
11.4.7 Has Potential for Peptide Resolution 360
11.4.8 Current Challenges and Future Directions 360
11.5 Fast Radical Footprinting for Protein Ligand Interaction
Analysis 361
11.5.1 Rationale for Hydroxyl Radicals as a Probe 362
11.5.2 Methods for Generating Hydroxyl Radicals 362
11.5.3 Fast Photochemical Oxidation of Proteins 363
11.5.4 Locating the Sites of Oxidation 364
11.5.5 Application of FPOP to Apomyoglobin 364
11.5.6 Advantages of FPOP 366
Contents I XIII
11.6 Potential Applications in Drug Discovery 367
References 368
12 Protein targeting Drug Discovery Guided by Hydrogen/Deuterium Exchange
Mass Spectrometry (DXMS) 377
Yoshitomo Hamuro, Stephen J. Coales, and Virgil L Woods Jr
12.1 Introduction 377
12.2 Theory of H/D Exchange 378
12.2.1 Amide H/D Exchange 378
12.2.2 Protection Factor 378
12.2.3 Backbone Amide Hydrogens as Thermodynamic Sensors 379
12.3 Overview of H/D Exchange Technologies 380
12.3.1 On Exchange Reaction 380
12.3.2 Quench of Exchange Reaction 380
12.3.3 Protein Fragmentation by Proteolysis 381
12.3.4 Digestion Optimization 381
12.3.5 HPLC Separation 381
12.3.6 Mass Analysis 381
12.37 Automation of H/D Exchange by MS 382
12.3.8 Automated Data Analysis 383
12.4 DXMS guided Design of Well Crystallizing Proteins 383
12.4.1 Disordered Regions and Protein Crystallography 383
12.4.2 Poorly Crystallizing Proteins Contain Substantial Disordered
Regions 384
12.4.3 Disorder depleted Mutant Preserved Ordered Structure 384
12.4.4 Disorder depleted Mutant Improved Crystallization Efficiency and
Produced High Resolution Structure 384
12.5 Rapid Characterization of Protein Conformational Change with
DXMS 385
12.5.1 Human Growth Hormone 386
12.5.2 H/D Exchange of hGH 386
12.5.3 Free Energy Change upon Folding of hGH 386
12.6 Application of H/D Exchange to Protein Small Molecule Ligand
Interactions 388
12.6.1 p38 Mitogen activated Protein Kinase 388
12.6.2 H/D Exchange of p38 MAP Kinase 389
12.6.3 Peroxisome Proliferator activated Receptor y 390
12.6.4 H/D Exchange of PPARy 390
12.7 DXMS guided Design of Small Molecules that Target Protein Protein
Interaction Surfaces 391
12.8 Optimal Formulation and Quality Control of Whole protein
Therapeutics with DXMS 393
12.9 Conclusions 394
References 394
XIV I Contents
V MS in early pharmacokinetics 399
13 Mass Spectrometry in Early Pharmacokinetic Investigations 401
Walter A. Korfmacher
13.1 Introduction 401
13.2 HPLC MS/MS Overview 402
13.3 In Vitro Applications 405
13.4 In Vivo Applications 406
13.5 Rapid Method Development 408
13.6 Increasing Throughput in HPLC MS/MS 410
13.7 Matrix Effects 411
13.8 Discovery PK Assay Rules 413
13.9 New Technology in LC MS 415
13.10 Conclusion 419
References 419
Index 429 |
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| illustrated | Illustrated |
| index_date | 2024-07-02T16:25:13Z |
| indexdate | 2024-07-20T09:10:13Z |
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| isbn | 9783527314560 3527314563 |
| language | English |
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| physical | XXI, 437 S. Ill., graph. Darst. |
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| series | Methods and principles in medicinal chemistry |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Mass spectrometry in medicinal chemistry ed. by Klaus T. Wanner ... Weinheim WILEY-VCH 2007 XXI, 437 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 36 Chemistry, Pharmaceutical methods Drug Design Drug development Mass Spectrometry methods Mass spectrometry Pharmaceutical Preparations analysis Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd rswk-swf Massenspektrometrie (DE-588)4037882-2 gnd rswk-swf Massenspektrometrie (DE-588)4037882-2 s Pharmazeutische Chemie (DE-588)4132158-3 s DE-604 Wanner, Klaus T. 1954- Sonstige (DE-588)110226615 oth Methods and principles in medicinal chemistry 36 (DE-604)BV035418617 36 text/html http://deposit.dnb.de/cgi-bin/dokserv?id=2856474&prov=M&dok_var=1&dok_ext=htm Inhaltstext HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=015416648&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Mass spectrometry in medicinal chemistry Methods and principles in medicinal chemistry Chemistry, Pharmaceutical methods Drug Design Drug development Mass Spectrometry methods Mass spectrometry Pharmaceutical Preparations analysis Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd Massenspektrometrie (DE-588)4037882-2 gnd |
| subject_GND | (DE-588)4132158-3 (DE-588)4037882-2 |
| title | Mass spectrometry in medicinal chemistry |
| title_auth | Mass spectrometry in medicinal chemistry |
| title_exact_search | Mass spectrometry in medicinal chemistry |
| title_exact_search_txtP | Mass spectrometry in medicinal chemistry |
| title_full | Mass spectrometry in medicinal chemistry ed. by Klaus T. Wanner ... |
| title_fullStr | Mass spectrometry in medicinal chemistry ed. by Klaus T. Wanner ... |
| title_full_unstemmed | Mass spectrometry in medicinal chemistry ed. by Klaus T. Wanner ... |
| title_short | Mass spectrometry in medicinal chemistry |
| title_sort | mass spectrometry in medicinal chemistry |
| topic | Chemistry, Pharmaceutical methods Drug Design Drug development Mass Spectrometry methods Mass spectrometry Pharmaceutical Preparations analysis Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd Massenspektrometrie (DE-588)4037882-2 gnd |
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