Details

Fragment-based Drug Discovery


Fragment-based Drug Discovery

Lessons and Outlook
Methods & Principles in Medicinal Chemistry 1. Aufl.

von: Daniel A. Erlanson, Wolfgang Jahnke, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

151,99 €

Verlag: Wiley-VCH
Format: EPUB
Veröffentl.: 02.12.2015
ISBN/EAN: 9783527683628
Sprache: englisch
Anzahl Seiten: 528

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Beschreibungen

<p>From its origins as a niche technique more than 15 years ago, fragment-based approaches have become a major tool for drug and ligand discovery, often yielding results where other methods have failed. Written by the pioneers in the field, this book provides a comprehensive overview of current methods and applications of fragment-based discovery, as well as an outlook on where the field is headed.</p> <p>The first part discusses basic considerations of when to use fragment-based methods, how to select targets, and how to build libraries in the chemical fragment space. The second part describes established, novel and emerging methods for fragment screening, including empirical as well as computational approaches. Special cases of fragment-based screening, e. g. for complex target systems and for covalent inhibitors are also discussed. The third part presents several case studies from recent and on-going drug discovery projects for a variety of target classes, from kinases and phosphatases to targeting protein-protein interaction and epigenetic targets.</p>
<p>Contributors XV</p> <p>Preface XXI</p> <p>A Personal Foreword XXIII</p> <p><b>Part I The Concept of Fragment-based Drug Discovery 1</b></p> <p><b>1 The Role of Fragment-based Discovery in Lead Finding 3</b><br /><i>Roderick E. Hubbard</i></p> <p>1.1 Introduction 3</p> <p>1.2 What is FBLD? 4</p> <p>1.3 FBLD: Current Practice 5</p> <p>1.3.1 Using Fragments: Conventional Targets 5</p> <p>1.3.2 Using Fragments: Unconventional Targets 13</p> <p>1.4 What do Fragments Bring to Lead Discovery? 14</p> <p>1.5 How did We Get Here? 16</p> <p>1.5.1 Evolution of the Early Ideas and History 16</p> <p>1.5.2 What has Changed Since the First Book was Published in 2006? 16</p> <p>1.6 Evolution of the Methods and Their Application Since 2005 19</p> <p>1.6.1 Developments in Fragment Libraries 21</p> <p>1.6.2 Fragment Hit Rate and Druggability 22</p> <p>1.6.3 Developments in Fragment Screening 23</p> <p>1.6.4 Ways of Evolving Fragments 23</p> <p>1.6.5 Integrating Fragments Alongside Other Lead-Finding Strategies 23</p> <p>1.6.6 Fragments Can be Selective 24</p> <p>1.6.7 Fragment Binding Modes 25</p> <p>1.6.8 Fragments, Chemical Space, and Novelty 27</p> <p>1.7 Current Application and Impact 27</p> <p>1.8 Future Opportunities 28</p> <p>References 29</p> <p><b>2 Selecting the Right Targets for Fragment-Based Drug Discovery 37</b><br /><i>Thomas G. Davies, Harren Jhoti, Puja Pathuri, and Glyn Williams</i></p> <p>2.1 Introduction 37</p> <p>2.2 Properties of Targets and Binding Sites 39</p> <p>2.3 Assessing Druggability 41</p> <p>2.4 Properties of Ligands and Drugs 42</p> <p>2.5 Case Studies 43</p> <p>2.5.1 Case Study 1: Inhibitors of Apoptosis Proteins (IAPs) 44</p> <p>2.5.2 Case Study 2: HCV-NS3 46</p> <p>2.5.3 Case Study 3: PKM2 47</p> <p>2.5.4 Case Study 4: Soluble Adenylate Cyclase 49</p> <p>2.6 Conclusions 50</p> <p>References 51</p> <p><b>3 Enumeration of Chemical Fragment Space 57</b><br /><i>Jean-Louis Reymond, Ricardo Visini, and Mahendra Awale</i></p> <p>3.1 Introduction 57</p> <p>3.2 The Enumeration of Chemical Space 58</p> <p>3.2.1 Counting and Sampling Approaches 58</p> <p>3.2.2 Enumeration of the Chemical Universe Database GDB 58</p> <p>3.2.3 GDB Contents 59</p> <p>3.3 Using and Understanding GDB 61</p> <p>3.3.1 Drug Discovery 61</p> <p>3.3.2 The MQN System 62</p> <p>3.3.3 Other Fingerprints 63</p> <p>3.4 Fragments from GDB 65</p> <p>3.4.1 Fragment Replacement 65</p> <p>3.4.2 Shape Diversity of GDB Fragments 66</p> <p>3.4.3 Aromatic Fragments from GDB 68</p> <p>3.5 Conclusions and Outlook 68</p> <p>Acknowledgment 69</p> <p>References 69</p> <p><b>4 Ligand Efficiency Metrics and their Use in Fragment Optimizations 75</b><br /><i>György G. Ferenczy and György M. Keseru</i></p> <p>4.1 Introduction 75</p> <p>4.2 Ligand Efficiency 75</p> <p>4.3 Binding Thermodynamics and Efficiency Indices 78</p> <p>4.4 Enthalpic Efficiency Indices 81</p> <p>4.5 Lipophilic Efficiency Indices 83</p> <p>4.6 Application of Efficiency Indices in Fragment-Based Drug Discovery Programs 88</p> <p>4.7 Conclusions 94</p> <p>References 95</p> <p><b>Part II Methods and Approaches for Fragment-based Drug Discovery 99</b></p> <p><b>5 Strategies for Fragment Library Design 101</b><br /><i>Justin Bower, Angelo Pugliese, and Martin Drysdale</i></p> <p>5.1 Introduction 101</p> <p>5.2 Aims 102</p> <p>5.3 Progress 102</p> <p>5.3.1 BDDP Fragment Library Design: Maximizing Diversity 103</p> <p>5.3.2 Assessing Three-Dimensionality 103</p> <p>5.3.3 3DFrag Consortium 104</p> <p>5.3.4 Commercial Fragment Space Analysis 105</p> <p>5.3.5 BDDP Fragment Library Design 108</p> <p>5.3.6 Fragment Complexity 111</p> <p>5.3.6.1 Diversity-Oriented Synthesis-Derived Fragment-Like Molecules 113</p> <p>5.4 Future Plans 114</p> <p>5.5 Summary 116</p> <p>5.6 Key Achievements 116</p> <p>References 116</p> <p><b>6 The Synthesis of Biophysical Methods In Support of Robust Fragment-Based Lead Discovery 119</b><br /><i>Ben J. Davis and Anthony M. Giannetti</i></p> <p>6.1 Introduction 119</p> <p>6.2 Fragment-Based Lead Discovery on a Difficult Kinase 121</p> <p>6.3 Application of Orthogonal Biophysical Methods to Identify and Overcome an Unusual Ligand: Protein Interaction 127</p> <p>6.4 Direct Comparison of Orthogonal Screening Methods Against a Well-Characterized Protein System 131</p> <p>6.5 Conclusions 135</p> <p>References 136</p> <p><b>7 Differential Scanning Fluorimetry as Part of a Biophysical Screening Cascade 139</b><br /><i>Duncan E. Scott, Christina Spry, and Chris Abell</i></p> <p>7.1 Introduction 139</p> <p>7.2 Theory 140</p> <p>7.2.1 Equilbria are Temperature Dependent 140</p> <p>7.2.2 Thermodynamics of Protein Unfolding 142</p> <p>7.2.3 Exact Mathematical Solutions to Ligand-Induced Thermal Shifts 143</p> <p>7.2.4 Ligand Binding and Protein Unfolding Thermodynamics Contribute to the Magnitude of Thermal Shifts 145</p> <p>7.2.5 Ligand Concentration and the Magnitude of Thermal Shifts 147</p> <p>7.2.6 Models of Protein Unfolding Equilibria and Ligand Binding 148</p> <p>7.2.7 Negative Thermal Shifts and General Confusions 150</p> <p>7.2.8 Lessons Learnt from Theoretical Analysis of DSF 151</p> <p>7.3 Practical Considerations for Applying DSF in Fragment-Based Approaches 152</p> <p>7.4 Application of DSF to Fragment-Based Drug Discovery 154</p> <p>7.4.1 DSF as a Primary Enrichment Technique 154</p> <p>7.4.2 DSF Compared with Other Hit Identification Techniques 159</p> <p>7.4.3 Pursuing Destabilizing Fragment Hits 166</p> <p>7.4.4 Lessons Learnt from Literature Examples of DSF in Fragment-Based Drug Discovery 168</p> <p>7.5 Concluding Remarks 169</p> <p>Acknowledgments 169</p> <p>References 170</p> <p><b>8 Emerging Technologies for Fragment Screening 173</b><br /><i>Sten Ohlson and Minh-Dao Duong-Thi</i></p> <p>8.1 Introduction 173</p> <p>8.2 Emerging Technologies 175</p> <p>8.2.1 Weak Affinity Chromatography 175</p> <p>8.2.1.1 Introduction 175</p> <p>8.2.1.2 Theory 177</p> <p>8.2.1.3 Fragment Screening 179</p> <p>8.2.2 Mass Spectrometry 185</p> <p>8.2.2.1 Introduction 185</p> <p>8.2.2.2 Theory 186</p> <p>8.2.2.3 Applications 186</p> <p>8.2.3 Microscale Thermophoresis 187</p> <p>8.2.3.1 Introduction 187</p> <p>8.2.3.2 Theory 189</p> <p>8.2.3.3 Applications 189</p> <p>8.3 Conclusions 189</p> <p>Acknowledgments 191</p> <p>References 191</p> <p><b>9 Computational Methods to Support Fragment-based Drug Discovery 197</b><br /><i>Laurie E. Grove, Sandor Vajda, and Dima Kozakov</i></p> <p>9.1 Computational Aspects of FBDD 197</p> <p>9.2 Detection of Ligand Binding Sites and Binding Hot Spots 198</p> <p>9.2.1 Geometry-based Methods 199</p> <p>9.2.2 Energy-based Methods 201</p> <p>9.2.3 Evolutionary and Structure-based Methods 202</p> <p>9.2.4 Combination Methods 202</p> <p>9.3 Assessment of Druggability 203</p> <p>9.4 Generation of Fragment Libraries 205</p> <p>9.4.1 Known Drugs 206</p> <p>9.4.2 Natural Compounds 207</p> <p>9.4.3 Novel Scaffolds 208</p> <p>9.5 Docking Fragments and Scoring 209</p> <p>9.5.1 Challenges of Fragment Docking 209</p> <p>9.5.2 Examples of Fragment Docking 210</p> <p>9.6 Expansion of Fragments 212</p> <p>9.7 Outlook 214</p> <p>References 214</p> <p><b>10 Making FBDD Work in Academia 223</b><br /><i>Stacie L. Bulfer, Frantz Jean-Francois, and Michelle R. Arkin</i></p> <p>10.1 Introduction 223</p> <p>10.2 How Academic and Industry Drug Discovery Efforts Differ 225</p> <p>10.3 The Making of a Good Academic FBDD Project 226</p> <p>10.4 FBDD Techniques Currently Used in Academia 228</p> <p>10.4.1 Nuclear Magnetic Resonance 229</p> <p>10.4.2 X-Ray Crystallography 230</p> <p>10.4.3 Surface Plasmon Resonance/Biolayer Interferometry 231</p> <p>10.4.4 Differential Scanning Fluorimetry 232</p> <p>10.4.5 Isothermal Titration Calorimetry 232</p> <p>10.4.6 Virtual Screening 232</p> <p>10.4.7 Mass Spectrometry 233</p> <p>10.4.7.1 Native MS 233</p> <p>10.4.7.2 Site-Directed Disulfide Trapping (Tethering) 234</p> <p>10.4.8 High-Concentration Bioassays 234</p> <p>10.5 Project Structures for Doing FBDD in Academia 235</p> <p>10.5.1 Targeting p97: A Chemical Biology Consortium Project 235</p> <p>10.5.2 Targeting Caspase-6: An Academic–Industry Partnership 236</p> <p>10.6 Conclusions and Perspectives 239</p> <p>References 240</p> <p><b>11 Site-Directed Fragment Discovery for Allostery 247</b><br /><i>T. Justin Rettenmaier, Sean A. Hudson, and James A. Wells</i></p> <p>11.1 Introduction 247</p> <p>11.2 Caspases 249</p> <p>11.2.1 Tethered Allosteric Inhibitors of Executioner Caspases-3 and -7 249</p> <p>11.2.2 Tethering Inflammatory Caspase-1 250</p> <p>11.2.3 Tethered Allosteric Inhibitors of Caspase-5 251</p> <p>11.2.4 General Allosteric Regulation at the Caspase Dimer Interface 252</p> <p>11.2.5 Using Disulfide Fragments as “Chemi-Locks” to Generate Conformation-Specific Antibodies 253</p> <p>11.3 Tethering K-Ras(G12C) 254</p> <p>11.4 The Master Transcriptional Coactivator CREB Binding Protein 256</p> <p>11.4.1 Tethering to Find Stabilizers of the KIX Domain of CBP 256</p> <p>11.4.2 Dissecting the Allosteric Coupling between Binding Sites on KIX 257</p> <p>11.4.3 Rapid Identification of pKID-Competitive Fragments for KIX 258</p> <p>11.5 Tethering Against the PIF Pocket of Phosphoinositide-Dependent Kinase 1 (PDK1) 259</p> <p>11.6 Tethering Against GPCRs: Complement 5A Receptor 261</p> <p>11.7 Conclusions and Future Directions 263</p> <p>References 264</p> <p><b>12 Fragment Screening in Complex Systems 267</b><br /><i>Miles Congreve and John A. Christopher</i></p> <p>12.1 Introduction 267</p> <p>12.2 Fragment Screening and Detection of Fragment Hits 268</p> <p>12.2.1 Fragment Screening Using NMR Techniques 270</p> <p>12.2.2 Fragment Screening Using Surface Plasmon Resonance 271</p> <p>12.2.3 Fragment Screening Using Capillary Electrophoresis 272</p> <p>12.2.4 Fragment Screening Using Radioligand and Fluorescence-Based Binding Assays 273</p> <p>12.2.5 Ion Channel Fragment Screening 275</p> <p>12.3 Validating Fragment Hits 276</p> <p>12.4 Fragment to Hit 279</p> <p>12.4.1 Fragment Evolution 280</p> <p>12.4.2 Fragment Linking 281</p> <p>12.5 Fragment to Lead Approaches 281</p> <p>12.5.1 Fragment Evolution 282</p> <p>12.5.2 Fragment Linking 284</p> <p>12.6 Perspective and Conclusions 285</p> <p>Acknowledgments 287</p> <p>References 287</p> <p><b>13 Protein-Templated Fragment Ligation Methods: Emerging Technologies in Fragment-Based Drug Discovery 293</b><br /><i>Mike Jaegle, Eric Nawrotzky, Ee Lin Wong, Christoph Arkona, and Jörg Rademann</i></p> <p>13.1 Introduction: Challenges and Visions in Fragment-Based Drug Discovery 293</p> <p>13.2 Target-Guided Fragment Ligation: Concepts and Definitions 294</p> <p>13.3 Reversible Fragment Ligation 295</p> <p>13.3.1 Dynamic Reversible Fragment Ligation Strategies 295</p> <p>13.3.2 Chemical Reactions Used in Dynamic Fragment Ligations 296</p> <p>13.3.3 Detection Strategies in Dynamic Fragment Ligations 299</p> <p>13.3.4 Applications of Dynamic Fragment Ligations in FBDD 301</p> <p>13.4 Irreversible Fragment Ligation 311</p> <p>13.4.1 Irreversible Fragment Ligation Strategies: Pros and Cons 311</p> <p>13.4.2 Detection in Irreversible Fragment Ligation 311</p> <p>13.4.3 Applications of Irreversible Fragment Ligations in FBDD 313</p> <p>13.5 Fragment Ligations Involving Covalent Reactions with Proteins 316</p> <p>13.6 Conclusions and Future Outlook: How Far did We Get and What will be Possible? 319</p> <p>References 320</p> <p><b>Part III Successes from Fragment-based Drug Discovery 327</b></p> <p><b>14 BACE Inhibitors 329</b><br /><i>Daniel F. Wyss, Jared N. Cumming, Corey O. Strickland, and Andrew W. Stamford</i></p> <p>14.1 Introduction 329</p> <p>14.2 FBDD Efforts on BACE1 333</p> <p>14.2.1 Fragment Hit Identification, Validation, and Expansion 333</p> <p>14.2.2 Fragment Optimization 333</p> <p>14.2.3 From a Key Pharmacophore to Clinical Candidates 340</p> <p>14.3 Conclusions 346</p> <p>References 346</p> <p><b>15 Epigenetics and Fragment-Based Drug Discovery 355</b><br /><i>Aman Iqbal and Peter J. Brown</i></p> <p>15.1 Introduction 355</p> <p>15.2 Epigenetic Families and Drug Targets 357</p> <p>15.3 Epigenetics Drug Discovery Approaches and Challenges 358</p> <p>15.4 FBDD Case Studies 359</p> <p>15.4.1 BRD4 (Bromodomain) 360</p> <p>15.4.2 EP300 (Bromodomain) 363</p> <p>15.4.3 ATAD2 (Bromodomain) 364</p> <p>15.4.4 BAZ2B (Bromodomain) 364</p> <p>15.4.5 SIRT2 (Histone Deacetylase) 365</p> <p>15.4.6 Next-Generation Epigenetic Targets: The “Royal Family” and Histone Demethylases 366</p> <p>15.5 Conclusions 367</p> <p>Abbreviations 368</p> <p>References 368</p> <p><b>16 Discovery of Inhibitors of Protein–Protein Interactions Using Fragment-Based Methods 371</b><br /><i>Feng Wang and Stephen W. Fesik</i></p> <p>16.1 Introduction 371</p> <p>16.2 Fragment-Based Strategies for Targeting PPIs 372</p> <p>16.2.1 Fragment Library Construction 372</p> <p>16.2.2 NMR-Based Fragment Screening Methods 373</p> <p>16.2.3 Structure Determination of Complexes 374</p> <p>16.2.4 Structure-Guided Hit-to-Lead Optimization 375</p> <p>16.3 Recent Examples from Our Laboratory 376</p> <p>16.3.1 Discovery of RPA Inhibitors 377</p> <p>16.3.2 Discovery of Potent Mcl-1 Inhibitors 378</p> <p>16.3.3 Discovery of Small Molecules that Bind to K-Ras 379</p> <p>16.4 Summary and Conclusions 382</p> <p>Acknowledgments 383</p> <p>References 384</p> <p><b>17 Fragment-Based Discovery of Inhibitors of Lactate Dehydrogenase A 391</b><br /><i>Alexander L. Breeze, Richard A. Ward, and Jon Winter</i></p> <p>17.1 Aerobic Glycolysis, Lactate Metabolism, and Cancer 391</p> <p>17.2 Lactate Dehydrogenase as a Cancer Target 392</p> <p>17.3 “Ligandability” Characteristics of the Cofactor and Substrate Binding Sites in LDHA 394</p> <p>17.4 Previously Reported LDH Inhibitors 395</p> <p>17.5 Fragment-Based Approach to LDHA Inhibition at AstraZeneca 398</p> <p>17.5.1 High-Throughput Screening Against LDHA 398</p> <p>17.5.2 Rationale and Strategy for Exploration of Fragment-Based Approaches 399</p> <p>17.5.3 Development of Our Biophysical and Structural Biology Platform 400</p> <p>17.5.4 Elaboration of Adenine Pocket Fragments 404</p> <p>17.5.5 Screening for Fragments Binding in the Substrate and Nicotinamide Pockets 405</p> <p>17.5.6 Reaching out Across the Void 407</p> <p>17.5.7 Fragment Linking and Optimization 408</p> <p>17.6 Fragment-Based LDHA Inhibitors from Other Groups 410</p> <p>17.6.1 Nottingham 410</p> <p>17.6.2 Ariad 413</p> <p>17.7 Conclusions and Future Perspectives 417</p> <p>References 419</p> <p><b>18 FBDD Applications to Kinase Drug Hunting 425</b><br /><i>Gordon Saxty</i></p> <p>18.1 Introduction 425</p> <p>18.2 Virtual Screening and X-ray for PI3K 426</p> <p>18.3 High-Concentration Screening and X-ray for Rock1/2 427</p> <p>18.4 Surface Plasmon Resonance for MAP4K4 428</p> <p>18.5 Weak Affinity Chromatography for GAK 429</p> <p>18.6 X-ray for CDK 4/6 430</p> <p>18.7 High-Concentration Screening, Thermal Shift, and X-ray for CHK2 432</p> <p>18.8 Virtual Screening and Computational Modeling for AMPK 433</p> <p>18.9 High-Concentration Screening, NMR, and X-ray FBDD for PDK1 434</p> <p>18.10 Tethering Mass Spectometry and X-ray for PDK1 435</p> <p>18.11 NMR and X-ray Case Study for Abl (Allosteric) 436</p> <p>18.12 Review of Current Kinase IND’s and Conclusions 437</p> <p>References 442</p> <p><b>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</b> <br /><i>Simon Rüdisser, Eric Vangrevelinghe, and Jürgen Maibaum</i></p> <p>19.1 Introduction 447</p> <p>19.2 Renin as a Drug Target 449</p> <p>19.3 The Catalytic Mechanism of Renin 451</p> <p>19.4 Virtual Screening 452</p> <p>19.5 Fragment-Based Lead Finding Applied to Renin and Other Aspartyl Proteases 455</p> <p>19.6 Renin Fragment Library Design 464</p> <p>19.7 Fragment Screening by NMR T1ρ Ligand Observation 469</p> <p>19.8 X-Ray Crystallography 473</p> <p>19.9 Renin Fragment Hit-to-Lead Evolution 475</p> <p>19.10 Integration of Fragment Hits and HTS Hits 476</p> <p>19.11 Conclusions 479</p> <p>References 480</p> <p>Index 487</p>
Daniel A. Erlanson is the co-founder and President of Carmot Therapeutics, Inc., which is developing fragment-based approaches to address unmet needs in drug discovery. Prior to Carmot, Dr. Erlanson worked in medicinal chemistry and technology development at Sunesis Pharmaceuticals, which he joined at the company's inception. Before Sunesis, he was an NIH postdoctoral fellow with Dr. James A. Wells at Genentech. Dr. Erlanson earned his Ph.D. in chemistry from Harvard University in the laboratory of Gregory L. Verdine and his BA in chemistry from Carleton College. He edits a blog devoted to fragment-based drug discovery, Practical Fragments.<br> <br> Wolfgang Jahnke is a Director and Leading Scientist at the Novartis Institutes for Biomedical Research in Basel, Switzerland. His major interests are Structural Biophysics and Fragment-based Drug Discovery. He has received several honors, among them the Industrial Investigator Award from the Swiss Chemical Society, and several Novartis-internal Awards. Dr. Jahnke received his PhD from the TU Munchen, working with Horst Kessler on the development and application of novel NMR methods. Prior to joining Novartis, he worked with Peter Wright at the Scripps Research Institute in La Jolla.<br>

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