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170328s2017 nju ob 001 0 eng |
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2017014921 |
| 020 ## - INTERNATIONAL STANDARD BOOK NUMBER |
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| International Standard Book Number |
9781119099499 (pdf) |
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9781119099505 (epub) |
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9781119099512 |
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| Original cataloging agency |
DLC |
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eng |
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rda |
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DLC |
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DLC |
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eng. |
| 042 ## - AUTHENTICATION CODE |
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pcc |
| 050 00 - LIBRARY OF CONGRESS CALL NUMBER |
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RS420 |
| 060 10 - NATIONAL LIBRARY OF MEDICINE CALL NUMBER |
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| Classification number |
QV 745 |
| 082 00 - DEWEY DECIMAL CLASSIFICATION NUMBER |
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| Classification number |
615.1/9 |
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23 |
| 245 00 - TITLE STATEMENT |
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| Title |
Applied biophysics for drug discovery / |
| Statement of responsibility, etc |
edited by Donald Huddler, Edward R. Zartler. |
| 264 #1 - PUBLICATION, DISTRIBUTION, ETC. (IMPRINT) |
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| Place of publication, distribution, etc |
Hoboken, NJ : |
| Name of publisher, distributor, etc |
Wiley, |
| Date of publication, distribution, etc |
2017. |
| 300 ## - PHYSICAL DESCRIPTION |
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1 online resource (312 pages). |
| 336 ## - CONTENT TYPE |
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rdacontent |
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text |
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txt |
| 337 ## - MEDIA TYPE |
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rdamedia |
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computer |
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c |
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rdacarrier |
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online resource |
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| 500 ## - GENERAL NOTE |
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| General note |
ABOUT THE AUTHOR<br/>Donald Huddler, Widener University Delaware Law School, Wilmington, USA.<br/><br/>Edward R. Zartler is Chief Scientific Officer at Quantum Tessera Consulting, LLC, USA. |
| 504 ## - BIBLIOGRAPHY, ETC. NOTE |
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| Bibliography, etc |
Includes bibliographical references and index. |
| 505 0# - CONTENTS |
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| Formatted contents note |
TABLE OF CONTENTS<br/>List of Contributors xiii<br/><br/>1 Introduction 1<br/>Donald Huddler<br/><br/>References 3<br/><br/>2 Thermodynamics in Drug Discovery 7<br/>Ronan O’Brien, Natalia Markova, and Geoffrey A. Holdgate<br/><br/>2.1 Introduction 7<br/><br/>2.2 Methods for Measuring Thermodynamics of Biomolecular Interactions 8<br/><br/>2.2.1 Direct Method: Isothermal Titration Calorimetry 8<br/><br/>2.2.2 Indirect Methods: van’t Hoff Analysis 8<br/><br/>2.2.2.1 Enthalpy Measurement Using van’t Hoff Analysis 8<br/><br/>2.3 Thermodynamic‐Driven Lead Optimization 9<br/><br/>2.3.1 The Thermodynamic Rules of Thumb 9<br/><br/>2.3.2 Enthalpy–Entropy Compensation 10<br/><br/>2.3.3 Enthalpy–Entropy Transduction 13<br/><br/>2.3.4 The Role of Water 14<br/><br/>2.4 Enthalpy as a Probe for Binding 15<br/><br/>2.4.1 Thermodynamics in Fragment‐Based Drug Design (FBDD) 15<br/><br/>2.4.2 Experimental Considerations and Limitations When Working with Fragments 16<br/><br/>2.4.3 Enthalpic Screening 17<br/><br/>2.5 Enthalpy as a Tool for Studying Complex Interactions 17<br/><br/>2.5.1 Identifying and Handling Complexity 17<br/><br/>2.6 Current and Future Prospects for Thermodynamics in Decision‐Making Processes 24<br/><br/>References 25<br/><br/>3 Tailoring Hit Identification and Qualification Methods for Targeting Protein–Protein Interactions 29<br/>Björn Walse, Andrew P. Turnbull, and Susan M. Boyd<br/><br/>3.1 Introduction 29<br/><br/>3.2 Structural Characteristics of PPI Interfaces 29<br/><br/>3.3 Screening Library Properties 31<br/><br/>3.3.1 Standard/Targeted Libraries/DOS 31<br/><br/>3.3.2 Fragment Libraries 33<br/><br/>3.3.3 Macrocyclic and Constrained Peptides 33<br/><br/>3.3.4 DNA‐Encoded Libraries 34<br/><br/>3.4 Hit‐Finding Strategies 34<br/><br/>3.4.1 Small‐Molecule Approaches 36<br/><br/>3.4.2 Peptide‐Based Approaches 38<br/><br/>3.4.3 In Silico Approaches 39<br/><br/>3.5 Druggability Assessment 39<br/><br/>3.5.1 Small Molecule: Ligand‐Based Approaches 41<br/><br/>3.5.2 Small Molecule: Protein Structure‐Based Approaches 41<br/><br/>3.6 Allosteric Inhibition of PPIs 42<br/><br/>3.7 Stabilization of PPIs 43<br/><br/>3.8 Case Studies 43<br/><br/>3.8.1 Primary Peptide Epitopes 43<br/><br/>3.8.1.1 Bromodomains 44<br/><br/>3.8.2 Secondary Structure Epitopes 46<br/><br/>3.8.2.1 Bcl‐2 46<br/><br/>3.8.2.2 p53/MDM2 47<br/><br/>3.8.3 Tertiary Structure Epitopes 47<br/><br/>3.8.3.1 CD80–CD28 48<br/><br/>3.8.3.2 IL‐17A 48<br/><br/>3.9 Summary 49<br/><br/>References 50<br/><br/>4 Hydrogen–Deuterium Exchange Mass Spectrometry in Drug Discovery - Theory, Practice and Future 61<br/>Thorleif Lavold, Roman Zubarev, and Juan Astorga‐Wells<br/><br/>4.1 General Principles 61<br/><br/>4.2 Parameters Affecting Deuterium Incorporation 63<br/><br/>4.2.1 Primary Sequence 63<br/><br/>4.2.2 Intramolecular Hydrogen Bonding 63<br/><br/>4.2.3 Solvent Accessibility 63<br/><br/>4.2.4 pH Value 63<br/><br/>4.3 Utilization of HDX MS 64<br/><br/>4.3.1 Binding Site and Structural Changes Characterization upon Ligand Binding 64<br/><br/>4.3.1.1 Protein Stability - Biosimilar Characterization 64<br/><br/>4.4 Practical Aspects of HDX MS 65<br/><br/>4.4.1 Labeling 66<br/><br/>4.4.1.1 Deuterium Oxide and Protein Concentration 66<br/><br/>4.4.1.2 Ligand/Protein Ratio 66<br/><br/>4.4.1.3 Incubation–Labeling Time 66<br/><br/>4.4.1.4 Careful Preparation of the Control Sample 66<br/><br/>4.4.2 Sample Analysis 66<br/><br/>4.4.3 Data Analysis 67<br/><br/>4.5 Advantages of HDX MS 67<br/><br/>4.6 Perspectives and Future Application of HDX MS 68<br/><br/>References 69<br/><br/>5 Microscale Thermophoresis in Drug Discovery 73<br/>Tanja Bartoschik, Melanie Maschberger, Alessandra Feoli, Timon André, Philipp Baaske, Stefan Duhr, and Dennis Breitsprecher<br/><br/>5.1 Microscale Thermophoresis 73<br/><br/>5.1.1 Theoretical Background 74<br/><br/>5.1.2 Added Values for Small‐Molecule Interaction Studies 76<br/><br/>5.1.2.1 Size‐Change Independent Binding Signals 76<br/><br/>5.1.2.2 Difficult Targets and Assay Conditions 78<br/><br/>5.1.2.3 Detection of Aggregation and Other Secondary Effects 80<br/><br/>5.1.2.4 Quantification of Thermodynamic Parameters by MST 80<br/><br/>5.2 MST‐Based Lead Discovery 82<br/><br/>5.2.1 Single‐Point Screening 82<br/><br/>5.2.2 Secondary Affinity‐Based Fragment Screening by MST 85<br/><br/>5.2.3 Hit Identification and Affinity Determination of Small‐Molecule Binders to p38 Alpha Kinase 87<br/><br/>References 87<br/><br/>6 SPR Screening: Applying the New Generation of SPR Hardware 93<br/>Kartik Narayan and Steven S. Carroll<br/><br/>6.1 Platforms for Screening 93<br/><br/>6.2 SensiQ Pioneer as a “OneStep” Solution for Hit Identification 95<br/><br/>6.3 Deprioritization of False Positives Arising from Compound Aggregation 99<br/><br/>6.4 Concluding Remarks 103<br/><br/>References 104<br/><br/>7 Weak Affinity Chromatography (WAC) 107<br/>Sten Ohlson and Minh‐Dao Duong‐Thi<br/><br/>7.1 Introduction 107<br/><br/>7.2 Theory of WAC 109<br/><br/>7.3 Virtual WAC 110<br/><br/>7.4 Equipment and Procedure 111<br/><br/>7.5 Validation of WAC 113<br/><br/>7.6 Applications 114<br/><br/>7.6.1 Inhibitors for Cholera Toxin 115<br/><br/>7.6.2 Drug/Hormone: Protein Binding 115<br/><br/>7.6.3 Analysis of Stereoisomers 119<br/><br/>7.6.4 Carbohydrate Analysis with Antibodies and Lectins 120<br/><br/>7.6.5 Fragment Screening 121<br/><br/>7.6.6 Membrane Proteins 122<br/><br/>7.7 Conclusions and Future Perspectives 124<br/><br/>Acknowledgments 125<br/><br/>References 125<br/><br/>8 1D NMR Methods for Hit Identification 131<br/>Mary J. Harner, Guille Metzler, Caroline A. Fanslau, Luciano Mueller, and William J. Metzler<br/><br/>8.1 Introduction 131<br/><br/>8.2 NMR Methods for Quality Control 131<br/><br/>8.2.1 Compound DMSO Stock Concentration Determination 132<br/><br/>8.2.2 Compound Solubility Measurements in Aqueous Buffer 134<br/><br/>8.2.3 Compound Structural Integrity 136<br/><br/>8.2.4 Protein Reagent Characterization 136<br/><br/>8.3 NMR Binding Assays 136<br/><br/>8.3.1 Saturation Transfer Difference Assay 138<br/><br/>8.3.2 T2 Relaxation Assay 140<br/><br/>8.3.3 WaterLOGSY Assay 141<br/><br/>8.3.4 19F Displacement Assay 142<br/><br/>8.4 Multiplexing 143<br/><br/>8.5 Specificity 144<br/><br/>8.6 Automation 146<br/><br/>8.7 Practical Considerations for NMR Binding Assays 146<br/><br/>8.7.1 Compound Libraries 146<br/><br/>8.7.2 Tube Selection and Filling 147<br/><br/>8.7.3 Buffers 148<br/><br/>8.7.4 Targets 149<br/><br/>8.7.5 Experiment Selection 150<br/><br/>8.8 Conclusions 151<br/><br/>References 151<br/><br/>9 Protein‐Based NMR Methods Applied to Drug Discovery 153<br/>Alessio Bortoluzzi and Alessio Ciulli<br/><br/>9.1 Introduction 153<br/><br/>9.2 Chemical Shift Perturbation 154<br/><br/>9.2.1 Using Chemical Shift Perturbation to Study a Binding Event Between a Protein and a Ligand 154<br/><br/>9.2.2 Tackling the High Molecular Weight Limit by Reducing Transverse Relaxation and by Selective Labeling Patterns 156<br/><br/>9.2.3 CSP as Tool for Screening Campaigns 157<br/><br/>9.2.4 Structure–Activity Relationship by NMR 160<br/><br/>9.3 Methods for Obtaining Structural Information on Protein–Ligand Complex 160<br/><br/>9.3.1 SOS‐NMR 161<br/><br/>9.3.2 NOE‐Matching 162<br/><br/>9.3.3 Paramagnetic NMR Spectroscopy 162<br/><br/>9.4 Recent and Innovative Examples of Protein‐Observed NMR Techniques Applied Drug Discovery 163<br/><br/>9.4.1 An NMR‐Based Conformational Assay to Aid the Drug Discovery Process 163<br/><br/>9.4.2 In‐Cell NMR Techniques Applied to Drug Discovery 165<br/><br/>9.4.3 Time‐Resolved NMR Spectroscopy as a Tool for Studying Inhibitors of Posttranslational Modification Enzymes 166<br/><br/>9.4.4 Protein‐Observed 19F NMR Spectroscopy 168<br/><br/>9.5 Conclusions and Future Perspectives 170<br/><br/>References 170<br/><br/>10 Applications of Ligand and Protein‐Observed NMR in Ligand Discovery 175<br/>Isabelle Krimm<br/><br/>10.1 Introduction 175<br/><br/>10.2 Ligand‐Observed NMR Experiments Based on the Overhauser Effect 176<br/><br/>10.2.1 Transferred NOE, ILOE, and INPHARMA Experiments 176<br/><br/>10.2.1.1 Principle of the Transferred 2D 1H‐1H NOESY Experiment 176<br/><br/>10.2.1.2 Fragment‐Based Screening Using 2D Tr‐NOESY Experiment 178<br/><br/>10.2.1.3 Elucidation of the Active Conformation of the Ligand Using 2D 1H‐1H NOESY Experiment 178<br/><br/>10.2.1.4 Design of Protein Inhibitors Using Interligand NOEs 178<br/><br/>10.2.1.5 Identification of the Ligand Binding Site and Binding Mode Using INPHARMA 178<br/><br/>10.2.1.6 Design of Protein Inhibitors Using INPHARMA with Protein–Peptide Complexes 179<br/><br/>10.2.1.7 Experimental Conditions of the 2D 1H‐1H NOESY Experiment 179<br/><br/>10.2.2 Saturation Transfer Difference Experiment 180<br/><br/>10.2.2.1 Principle of the STD Experiment 180<br/><br/>10.2.2.2 Detection of Interactions and Library Screening by STD 180<br/><br/>10.2.2.3 Epitope Mapping by STD 181<br/><br/>10.2.2.4 Affinity Measurement by STD 181<br/><br/>10.2.2.5 Quantitative STD Using CORCEMA 183<br/><br/>10.2.2.6 Experimental Conditions 183<br/><br/>10.2.3 WaterLOGSY Experiment 184<br/><br/>10.2.3.1 Principle of the WaterLOGSY Experiment 184<br/><br/>10.2.3.2 Screening and Affinity Measurement by WaterLOGSY 184<br/><br/>10.2.3.3 Epitope Mapping and Water Accessibility in Protein–Ligand Complexes by WaterLOGSY 184<br/><br/>10.2.3.4 Experimental Conditions 185<br/><br/>10.3 Protein‐Observed NMR Experiments: Chemical Shift Perturbations 185<br/><br/>10.3.1 Principle 185<br/><br/>10.3.2 Affinity Measurement Using CSPs 186<br/><br/>10.3.3 Localization of Binding Sites Using CSPs 186<br/><br/>10.3.3.1 Chemical Shift Mapping 186<br/><br/>10.3.3.2 J‐Surface Modeling 187<br/><br/>10.3.4 Comparison of CSPs from Analogous Ligands 187<br/><br/>10.3.5 Back‐Calculation of Ligand‐Induced CSPs for Ligand Docking 187<br/><br/>10.3.5.1 CSP‐Based Post‐Docking Filter 189<br/><br/>10.3.5.2 CSP‐Guided Docking 189<br/><br/>10.4 Conclusion 189<br/><br/>Acknowledgments 191<br/><br/>References 191<br/><br/>11 Using Biophysical Methods to Optimize Compound Residence Time 197<br/>Geoffrey A. Holdgate, Philip Rawlins, Michal Bista, and Christopher J. Stubbs<br/><br/>11.1 Introduction 197<br/><br/>11.2 Biophysical Methods for Measuring Ligand Binding Kinetics 197<br/><br/>11.3 Measuring Structure–Kinetic Relationships: Some Example Case Studies 200<br/><br/>11.4 Effects of Conformational Dynamics on Binding Kinetics 201<br/><br/>11.5 Kinetic Selectivity 204<br/><br/>11.6 Mechanism of Binding and Kinetics 207<br/><br/>11.7 Optimizing Residence Time 207<br/><br/>11.8 Role of BK in Improving Efficacy 209<br/><br/>11.9 Effect of Pharmacokinetics and Pharmacodynamics 210<br/><br/>11.10 Summary 212<br/><br/>References 213<br/><br/>12 Applying Biophysical and Biochemical Methods to the Discovery of Allosteric Modulators of the AAA ATPase p97 217<br/>Stacie L. Bulfer and Michelle R. Arkin<br/><br/>12.1 p97 and Proteostasis Regulation 217<br/><br/>12.2 Structure and Dynamics of p97 218<br/><br/>12.3 Drug Discovery Efforts against p97 222<br/><br/>12.4 Uncompetitive Inhibitors of p97 Discovered by High‐Throughput Screening 223<br/><br/>12.4.1 Biochemical MOA Studies 223<br/><br/>12.4.2 Surface Plasmon Resonance 225<br/><br/>12.4.3 Nuclear Magnetic Resonance 226<br/><br/>12.4.4 Cryo‐EM Defines the Binding Site for an Uncompetitive Inhibitor of p97 228<br/><br/>12.4.5 Effect of Inhibitors on p97 PPI and MSP1 Disease Mutations 231<br/><br/>12.5 Fragment‐ Based Ligand Screening 231<br/><br/>12.5.1 Targeting the ND1 Domains 232<br/><br/>12.5.2 Targeting the N‐Domain 233<br/><br/>12.6 Conclusions 234<br/><br/>References 234<br/><br/>13 Driving Drug Discovery with Biophysical Information: Application to Staphylococcus aureus Dihydrofolate Reductase (DHFR) 241<br/>Parag Sahasrabudhe, Veerabahu Shanmugasundaram, Mark Flanagan, Kris A. Borzilleri, Holly Heaslet, Anil Rane, Alex McColl, Tim Subashi, George Karam, Ron Sarver, Melissa Harris, Boris A.Chrunyk, Chakrapani Subramanyam, Thomas V. Magee, Kelly Fahnoe, Brian Lacey, Henry Putz, J. Richard Miller, Jaehyun Cho, Arthur Palmer III, and Jane M. Withka<br/><br/>13.1 Introduction 241<br/><br/>13.2 Results and Discussion 245<br/><br/>13.2.1 Protein Dynamics of SA WT and S1 Mutant DHFR in Apo and Bound States 245<br/><br/>13.2.2 Protein Backbone 15N, 13C, and 1H NMR Resonance Assignments 246<br/><br/>13.2.3 Protein Residues Show Severe Line Broadening due to Conformational Exchange 246<br/><br/>13.2.4 R2 Relaxation Dispersion NMR Experiments 248<br/><br/>13.2.5 Kinetic Profiling of DHFR Inhibitors 251<br/><br/>13.2.6 Characterization of SA WT and S1 Mutant DHFR–TMP Interactions in Solution 253<br/><br/>13.2.7 Prospective Biophysics Library Design 254<br/><br/>13.3 Conclusion 258<br/><br/>References 259<br/><br/>14 Assembly of Fragment Screening Libraries: Property and Diversity Analysis 263<br/>Bradley C. Doak, Craig J. Morton, Jamie S. Simpson, and Martin J. Scanlon<br/><br/>14.1 Introduction 263<br/><br/>14.2 Physicochemical Properties of Fragments 265<br/><br/>14.3 Molecular Diversity and Its Assessment 268<br/><br/>14.4 Experimental Evaluation of Fragments 274<br/><br/>14.5 Assembling Libraries for Screening 275<br/><br/>14.6 Concluding Remarks 279<br/><br/>References 280<br/><br/>Index 285 |
| 520 ## - SUMMARY, ETC. |
|---|
| Summary, etc |
Applied Biophysics for Drug Discovery is a guide to new techniques and approaches to identifying and characterizing small molecules in early drug discovery. Biophysical methods are reasserting their utility in drug discovery and through a combination of the rise of fragment-based drug discovery and an increased focus on more nuanced characterisation of small molecule binding, these methods are playing an increasing role in discovery campaigns. <br/><br/>This text emphasizes practical considerations for selecting and deploying core biophysical method, including but not limited to ITC, SPR, and both ligand-detected and protein-detected NMR.<br/><br/>Topics covered include:<br/><br/>• Design considerations in biophysical-based lead screening<br/><br/>• Thermodynamic characterization of protein-compound interactions<br/><br/>• Characterizing targets and screening reagents with HDX-MS<br/><br/>• Microscale thermophoresis methods (MST)<br/><br/>• Screening with Weak Affinity Chromatography<br/><br/>• Methods to assess compound residence time<br/><br/>• 1D-NMR methods for hit identification<br/><br/>• Protein-based NMR methods for SAR development<br/><br/>• Industry case studies integrating multiple biophysical methods<br/><br/>This text is ideal for academic investigators and industry scientists planning hit characterization campaigns or designing and optimizing screening strategies. |
| 526 ## - STUDY PROGRAM INFORMATION NOTE |
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| -- |
600-699 |
| -- |
615 |
| 588 ## - SOURCE OF DESCRIPTION NOTE |
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| Source of description note |
Description based on print version record and CIP data provided by publisher. |
| 650 12 - SUBJECT ADDED ENTRY--TOPICAL TERM |
|---|
| Topical term or geographic name as entry element |
Drug Discovery |
| General subdivision |
methods |
| 650 22 - SUBJECT ADDED ENTRY--TOPICAL TERM |
|---|
| Topical term or geographic name as entry element |
Biophysical Phenomena |
| 655 #4 - INDEX TERM--GENRE/FORM |
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| Genre/form data or focus term |
Electronic books. |
| 700 1# - ADDED ENTRY--PERSONAL NAME |
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| Personal name |
Huddler, Donald Preston, |
| Dates associated with a name |
1971- |
| Relator term |
editor. |
| 700 1# - ADDED ENTRY--PERSONAL NAME |
|---|
| Personal name |
Zartler, Edward, |
| Relator term |
editor. |
| 856 ## - ELECTRONIC LOCATION AND ACCESS |
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| Link text |
Full text available at Wiley Online Library Click here to view |
| Uniform Resource Identifier |
https://onlinelibrary.wiley.com/doi/book/10.1002/9781119099512 |
| 942 ## - ADDED ENTRY ELEMENTS |
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| Source of classification or shelving scheme |
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| Item type |
EBOOK |