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Fragment-based drug discovery : lessons and outlook

Author: Daniel A Erlanson; Wolfgang Jahnke
Publisher: Weinheim : Wiley-VCH, 2015.
Series: Methods and principles in medicinal chemistry.
Edition/Format:   eBook : Document : EnglishView all editions and formats
Summary:

The secret of success in drug discovery written by the pioneers in the field with unrivaled experience in fragment-based methods. In this handbook, the first-hand knowledge imparted by the  Read more...

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Genre/Form: Electronic books
Additional Physical Format: Erscheint auch als:
Fragment-based drug discovery
Weinheim : Wiley-VCH Verlag GmbH & Co. KG, 2016
XXIV, 500 Seiten
Druckausgabe
Material Type: Document, Internet resource
Document Type: Internet Resource, Computer File
All Authors / Contributors: Daniel A Erlanson; Wolfgang Jahnke
ISBN: 9783527683628 3527683623 9783527683611 3527683615 9783527683604 3527683607
OCLC Number: 931873455
Description: 1 online resource.
Contents: Contributors XV Preface XXI A Personal Foreword XXIII Part I The Concept of Fragment-based Drug Discovery 1 1 The Role of Fragment-based Discovery in Lead Finding 3 Roderick E. Hubbard 1.1 Introduction 3 1.2 What is FBLD? 4 1.3 FBLD: Current Practice 5 1.3.1 Using Fragments: Conventional Targets 5 1.3.2 Using Fragments: Unconventional Targets 13 1.4 What do Fragments Bring to Lead Discovery? 14 1.5 How did We Get Here? 16 1.5.1 Evolution of the Early Ideas and History 16 1.5.2 What has Changed Since the First Book was Published in 2006? 16 1.6 Evolution of the Methods and Their Application Since 2005 19 1.6.1 Developments in Fragment Libraries 21 1.6.2 Fragment Hit Rate and Druggability 22 1.6.3 Developments in Fragment Screening 23 1.6.4 Ways of Evolving Fragments 23 1.6.5 Integrating Fragments Alongside Other Lead-Finding Strategies 23 1.6.6 Fragments Can be Selective 24 1.6.7 Fragment Binding Modes 25 1.6.8 Fragments, Chemical Space, and Novelty 27 1.7 Current Application and Impact 27 1.8 Future Opportunities 28 References 29 2 Selecting the Right Targets for Fragment-Based Drug Discovery 37 Thomas G. Davies, Harren Jhoti, Puja Pathuri, and Glyn Williams 2.1 Introduction 37 2.2 Properties of Targets and Binding Sites 39 2.3 Assessing Druggability 41 2.4 Properties of Ligands and Drugs 42 2.5 Case Studies 43 2.5.1 Case Study 1: Inhibitors of Apoptosis Proteins (IAPs) 44 2.5.2 Case Study 2: HCV-NS3 46 2.5.3 Case Study 3: PKM2 47 2.5.4 Case Study 4: Soluble Adenylate Cyclase 49 2.6 Conclusions 50 References 51 3 Enumeration of Chemical Fragment Space 57 Jean-Louis Reymond, Ricardo Visini, and Mahendra Awale 3.1 Introduction 57 3.2 The Enumeration of Chemical Space 58 3.2.1 Counting and Sampling Approaches 58 3.2.2 Enumeration of the Chemical Universe Database GDB 58 3.2.3 GDB Contents 59 3.3 Using and Understanding GDB 61 3.3.1 Drug Discovery 61 3.3.2 The MQN System 62 3.3.3 Other Fingerprints 63 3.4 Fragments from GDB 65 3.4.1 Fragment Replacement 65 3.4.2 Shape Diversity of GDB Fragments 66 3.4.3 Aromatic Fragments from GDB 68 3.5 Conclusions and Outlook 68 Acknowledgment 69 References 69 4 Ligand Efficiency Metrics and their Use in Fragment Optimizations 75 Gyorgy G. Ferenczy and Gyorgy M. Keseru 4.1 Introduction 75 4.2 Ligand Efficiency 75 4.3 Binding Thermodynamics and Efficiency Indices 78 4.4 Enthalpic Efficiency Indices 81 4.5 Lipophilic Efficiency Indices 83 4.6 Application of Efficiency Indices in Fragment-Based Drug Discovery Programs 88 4.7 Conclusions 94 References 95 Part II Methods and Approaches for Fragment-based Drug Discovery 99 5 Strategies for Fragment Library Design 101 Justin Bower, Angelo Pugliese, and Martin Drysdale 5.1 Introduction 101 5.2 Aims 102 5.3 Progress 102 5.3.1 BDDP Fragment Library Design: Maximizing Diversity 103 5.3.2 Assessing Three-Dimensionality 103 5.3.3 3DFrag Consortium 104 5.3.4 Commercial Fragment Space Analysis 105 5.3.5 BDDP Fragment Library Design 108 5.3.6 Fragment Complexity 111 5.3.6.1 Diversity-Oriented Synthesis-Derived Fragment-Like Molecules 113 5.4 Future Plans 114 5.5 Summary 116 5.6 Key Achievements 116 References 116 6 The Synthesis of Biophysical Methods In Support of Robust Fragment-Based Lead Discovery 119 Ben J. Davis and Anthony M. Giannetti 6.1 Introduction 119 6.2 Fragment-Based Lead Discovery on a Difficult Kinase 121 6.3 Application of Orthogonal Biophysical Methods to Identify and Overcome an Unusual Ligand: Protein Interaction 127 6.4 Direct Comparison of Orthogonal Screening Methods Against a Well-Characterized Protein System 131 6.5 Conclusions 135 References 136 7 Differential Scanning Fluorimetry as Part of a Biophysical Screening Cascade 139 Duncan E. Scott, Christina Spry, and Chris Abell 7.1 Introduction 139 7.2 Theory 140 7.2.1 Equilbria are Temperature Dependent 140 7.2.2 Thermodynamics of Protein Unfolding 142 7.2.3 Exact Mathematical Solutions to Ligand-Induced Thermal Shifts 143 7.2.4 Ligand Binding and Protein Unfolding Thermodynamics Contribute to the Magnitude of Thermal Shifts 145 7.2.5 Ligand Concentration and the Magnitude of Thermal Shifts 147 7.2.6 Models of Protein Unfolding Equilibria and Ligand Binding 148 7.2.7 Negative Thermal Shifts and General Confusions 150 7.2.8 Lessons Learnt from Theoretical Analysis of DSF 151 7.3 Practical Considerations for Applying DSF in Fragment-Based Approaches 152 7.4 Application of DSF to Fragment-Based Drug Discovery 154 7.4.1 DSF as a Primary Enrichment Technique 154 7.4.2 DSF Compared with Other Hit Identification Techniques 159 7.4.3 Pursuing Destabilizing Fragment Hits 166 7.4.4 Lessons Learnt from Literature Examples of DSF in Fragment-Based Drug Discovery 168 7.5 Concluding Remarks 169 Acknowledgments 169 References 170 8 Emerging Technologies for Fragment Screening 173 Sten Ohlson and Minh-Dao Duong-Thi 8.1 Introduction 173 8.2 Emerging Technologies 175 8.2.1 Weak Affinity Chromatography 175 8.2.1.1 Introduction 175 8.2.1.2 Theory 177 8.2.1.3 Fragment Screening 179 8.2.2 Mass Spectrometry 185 8.2.2.1 Introduction 185 8.2.2.2 Theory 186 8.2.2.3 Applications 186 8.2.3 Microscale Thermophoresis 187 8.2.3.1 Introduction 187 8.2.3.2 Theory 189 8.2.3.3 Applications 189 8.3 Conclusions 189 Acknowledgments 191 References 191 9 Computational Methods to Support Fragment-based Drug Discovery 197 Laurie E. Grove, Sandor Vajda, and Dima Kozakov 9.1 Computational Aspects of FBDD 197 9.2 Detection of Ligand Binding Sites and Binding Hot Spots 198 9.2.1 Geometry-based Methods 199 9.2.2 Energy-based Methods 201 9.2.3 Evolutionary and Structure-based Methods 202 9.2.4 Combination Methods 202 9.3 Assessment of Druggability 203 9.4 Generation of Fragment Libraries 205 9.4.1 Known Drugs 206 9.4.2 Natural Compounds 207 9.4.3 Novel Scaffolds 208 9.5 Docking Fragments and Scoring 209 9.5.1 Challenges of Fragment Docking 209 9.5.2 Examples of Fragment Docking 210 9.6 Expansion of Fragments 212 9.7 Outlook 214 References 214 10 Making FBDD Work in Academia 223 Stacie L. Bulfer, Frantz Jean-Francois, and Michelle R. Arkin 10.1 Introduction 223 10.2 How Academic and Industry Drug Discovery Efforts Differ 225 10.3 The Making of a Good Academic FBDD Project 226 10.4 FBDD Techniques Currently Used in Academia 228 10.4.1 Nuclear Magnetic Resonance 229 10.4.2 X-Ray Crystallography 230 10.4.3 Surface Plasmon Resonance/Biolayer Interferometry 231 10.4.4 Differential Scanning Fluorimetry 232 10.4.5 Isothermal Titration Calorimetry 232 10.4.6 Virtual Screening 232 10.4.7 Mass Spectrometry 233 10.4.7.1 Native MS 233 10.4.7.2 Site-Directed Disulfide Trapping (Tethering) 234 10.4.8 High-Concentration Bioassays 234 10.5 Project Structures for Doing FBDD in Academia 235 10.5.1 Targeting p97: A Chemical Biology Consortium Project 235 10.5.2 Targeting Caspase-6: An Academic Industry Partnership 236 10.6 Conclusions and Perspectives 239 References 240 11 Site-Directed Fragment Discovery for Allostery 247 T. Justin Rettenmaier, Sean A. Hudson, and James A. Wells 11.1 Introduction 247 11.2 Caspases 249 11.2.1 Tethered Allosteric Inhibitors of Executioner Caspases-3 and -7 249 11.2.2 Tethering Inflammatory Caspase-1 250 11.2.3 Tethered Allosteric Inhibitors of Caspase-5 251 11.2.4 General Allosteric Regulation at the Caspase Dimer Interface 252 11.2.5 Using Disulfide Fragments as Chemi-Locks to Generate Conformation-Specific Antibodies 253 11.3 Tethering K-Ras(G12C) 254 11.4 The Master Transcriptional Coactivator CREB Binding Protein 256 11.4.1 Tethering to Find Stabilizers of the KIX Domain of CBP 256 11.4.2 Dissecting the Allosteric Coupling between Binding Sites on KIX 257 11.4.3 Rapid Identification of pKID-Competitive Fragments for KIX 258 11.5 Tethering Against the PIF Pocket of Phosphoinositide-Dependent Kinase 1 (PDK1) 259 11.6 Tethering Against GPCRs: Complement 5A Receptor 261 11.7 Conclusions and Future Directions 263 References 264 12 Fragment Screening in Complex Systems 267 Miles Congreve and John A. Christopher 12.1 Introduction 267 12.2 Fragment Screening and Detection of Fragment Hits 268 12.2.1 Fragment Screening Using NMR Techniques 270 12.2.2 Fragment Screening Using Surface Plasmon Resonance 271 12.2.3 Fragment Screening Using Capillary Electrophoresis 272 12.2.4 Fragment Screening Using Radioligand and Fluorescence-Based Binding Assays 273 12.2.5 Ion Channel Fragment Screening 275 12.3 Validating Fragment Hits 276 12.4 Fragment to Hit 279 12.4.1 Fragment Evolution 280 12.4.2 Fragment Linking 281 12.5 Fragment to Lead Approaches 281 12.5.1 Fragment Evolution 282 12.5.2 Fragment Linking 284 12.6 Perspective and Conclusions 285 Acknowledgments 287 References 287 13 Protein-Templated Fragment Ligation Methods: Emerging Technologies in Fragment-Based Drug Discovery 293 Mike Jaegle, Eric Nawrotzky, Ee Lin Wong, Christoph Arkona, and Jorg Rademann 13.1 Introduction: Challenges and Visions in Fragment-Based Drug Discovery 293 13.2 Target-Guided Fragment Ligation: Concepts and Definitions 294 13.3 Reversible Fragment Ligation 295 13.3.1 Dynamic Reversible Fragment Ligation Strategies 295 13.3.2 Chemical Reactions Used in Dynamic Fragment Ligations 296 13.3.3 Detection Strategies in Dynamic Fragment Ligations 299 13.3.4 Applications of Dynamic Fragment Ligations in FBDD 301 13.4 Irreversible Fragment Ligation 311 13.4.1 Irreversible Fragment Ligation Strategies: Pros and Cons 311 13.4.2 Detection in Irreversible Fragment Ligation 311 13.4.3 Applications of Irreversible Fragment Ligations in FBDD 313 13.5 Fragment Ligations Involving Covalent Reactions with Proteins 316 13.6 Conclusions and Future Outlook: How Far did We Get and What will be Possible? 319 References 320 Part III Successes from Fragment-based Drug Discovery 327 14 BACE Inhibitors 329 Daniel F. Wyss, Jared N. Cumming, Corey O. Strickland, and Andrew W. Stamford 14.1 Introduction 329 14.2 FBDD Efforts on BACE1 333 14.2.1 Fragment Hit Identification, Validation, and Expansion 333 14.2.2 Fragment Optimization 333 14.2.3 From a Key Pharmacophore to Clinical Candidates 340 14.3 Conclusions 346 References 346 15 Epigenetics and Fragment-Based Drug Discovery 355 Aman Iqbal and Peter J. Brown 15.1 Introduction 355 15.2 Epigenetic Families and Drug Targets 357 15.3 Epigenetics Drug Discovery Approaches and Challenges 358 15.4 FBDD Case Studies 359 15.4.1 BRD4 (Bromodomain) 360 15.4.2 EP300 (Bromodomain) 363 15.4.3 ATAD2 (Bromodomain) 364 15.4.4 BAZ2B (Bromodomain) 364 15.4.5 SIRT2 (Histone Deacetylase) 365 15.4.6 Next-Generation Epigenetic Targets: The Royal Family and Histone Demethylases 366 15.5 Conclusions 367 Abbreviations 368 References 368 16 Discovery of Inhibitors of Protein Protein Interactions Using Fragment-Based Methods 371 Feng Wang and Stephen W. Fesik 16.1 Introduction 371 16.2 Fragment-Based Strategies for Targeting PPIs 372 16.2.1 Fragment Library Construction 372 16.2.2 NMR-Based Fragment Screening Methods 373 16.2.3 Structure Determination of Complexes 374 16.2.4 Structure-Guided Hit-to-Lead Optimization 375 16.3 Recent Examples from Our Laboratory 376 16.3.1 Discovery of RPA Inhibitors 377 16.3.2 Discovery of Potent Mcl-1 Inhibitors 378 16.3.3 Discovery of Small Molecules that Bind to K-Ras 379 16.4 Summary and Conclusions 382 Acknowledgments 383 References 384 17 Fragment-Based Discovery of Inhibitors of Lactate Dehydrogenase A 391 Alexander L. Breeze, Richard A. Ward, and Jon Winter 17.1 Aerobic Glycolysis, Lactate Metabolism, and Cancer 391 17.2 Lactate Dehydrogenase as a Cancer Target 392 17.3 Ligandability Characteristics of the Cofactor and Substrate Binding Sites in LDHA 394 17.4 Previously Reported LDH Inhibitors 395 17.5 Fragment-Based Approach to LDHA Inhibition at AstraZeneca 398 17.5.1 High-Throughput Screening Against LDHA 398 17.5.2 Rationale and Strategy for Exploration of Fragment-Based Approaches 399 17.5.3 Development of Our Biophysical and Structural Biology Platform 400 17.5.4 Elaboration of Adenine Pocket Fragments 404 17.5.5 Screening for Fragments Binding in the Substrate and Nicotinamide Pockets 405 17.5.6 Reaching out Across the Void 407 17.5.7 Fragment Linking and Optimization 408 17.6 Fragment-Based LDHA Inhibitors from Other Groups 410 17.6.1 Nottingham 410 17.6.2 Ariad 413 17.7 Conclusions and Future Perspectives 417 References 419 18 FBDD Applications to Kinase Drug Hunting 425 Gordon Saxty 18.1 Introduction 425 18.2 Virtual Screening and X-ray for PI3K 426 18.3 High-Concentration Screening and X-ray for Rock1/2 427 18.4 Surface Plasmon Resonance for MAP4K4 428 18.5 Weak Affinity Chromatography for GAK 429 18.6 X-ray for CDK 4/6 430 18.7 High-Concentration Screening, Thermal Shift, and X-ray for CHK2 432 18.8 Virtual Screening and Computational Modeling for AMPK 433 18.9 High-Concentration Screening, NMR, and X-ray FBDD for PDK1 434 18.10 Tethering Mass Spectometry and X-ray for PDK1 435 18.11 NMR and X-ray Case Study for Abl (Allosteric) 436 18.12 Review of Current Kinase IND s and Conclusions 437 References 442 19 An Integrated Approach for Fragment-Based Lead Discovery: Virtual, NMR, and High-Throughput Screening Combined with Structure-Guided Design. Application to the Aspartyl Protease Renin 447 Simon Rudisser, Eric Vangrevelinghe, and Jurgen Maibaum 19.1 Introduction 447 19.2 Renin as a Drug Target 449 19.3 The Catalytic Mechanism of Renin 451 19.4 Virtual Screening 452 19.5 Fragment-Based Lead Finding Applied to Renin and Other Aspartyl Proteases 455 19.6 Renin Fragment Library Design 464 19.7 Fragment Screening by NMR T1 Ligand Observation 469 19.8 X-Ray Crystallography 473 19.9 Renin Fragment Hit-to-Lead Evolution 475 19.10 Integration of Fragment Hits and HTS Hits 476 19.11 Conclusions 479 References 480 Index 487
Series Title: Methods and principles in medicinal chemistry.
Responsibility: edited by Daniel A. Erlanson and Wolfgang Jahnke.

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