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Lead Generation: Methods and Strategies

Jörg Holenz (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-33329-5
824 pages
June 2016
Lead Generation: Methods and Strategies (3527333290) cover image

Description

In this comprehensive two-volume resource on the topic senior lead generation medicinal chemists present a coherent view of the current methods and strategies in industrial and academic lead generation. This is the first book to combine both standard and innovative approaches in comparable breadth and depth, including several recent successful lead generation case studies published here for the first time.
Beginning with a general discussion of the underlying principles and strategies, individual lead generation approaches are described in detail, highlighting their strengths and weaknesses, along with all relevant bordering disciplines like e.g. target identification and validation, predictive methods, molecular recognition or lead quality matrices. Novel lead generation approaches for challenging targets like DNA-encoded library screening or chemical biology approaches are treated here side by side with established methods as high throughput and affinity screening, knowledge- or fragment-based lead generation, and collaborative approaches. Within the entire book, a very strong focus is given to highlight the application of the presented methods, so that the reader will be able to learn from real life examples. The final part of the book presents several lead generation case studies taken from different therapeutic fields, including diabetes, cardiovascular and respiratory diseases, neuroscience, infection and tropical diseases.
The result is a prime knowledge resource for medicinal chemists and for every scientist involved in lead generation.
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Table of Contents

Dedication V

List of Contributors XXI

Preface XXVII

A Personal Foreword XXXI

Volume 68a

Part I Introduction to Lead Generation 1

1 Introduction: Learnings from the Past – Characteristics of Successful Leads 3
Mike Hann

Acknowledgments 10

References 10

2 Modern Lead Generation Strategies 13
Jörg Holenz and Dean G. Brown

2.1 Lead Generation Greatly Influences Clinical Candidate Quality 14

2.2 Screening of Compound Libraries has Undergone a Major Paradigm Change 15

2.3 New Chemical Modalities are Available to Tackle Difficult Targets 15

2.4 As Demands have Increased, New Lead Generation Methods Emerged 16

2.5 How do Lead Generation Chemists Meet These Challenges and Subsequently Provide Their Lead Optimization Colleagues with High-Quality Lead Series? 17

2.5.1 Learnings can be Drawn from LG Project Failures 17

2.5.2 How Many Compounds to Screen to Generate High-Quality Leads? 18

2.5.3 Which Compounds to Screen to Generate High-Quality Leads? 19

2.5.4 Developing Project-Customized, Concerted, and Comprehensive Lead Generation Strategies will Increase LG Success Rates: the CREATION of Leads 20

2.5.5 Selecting the Target Defines LG Success Rates 21

2.5.6 Lead Generation should be Complemented by Auxiliary Technologies to Characterize Hits 21

2.5.7 Phenotypic Screens are Often Complemented by a Chemical Biology Arm 22

2.5.8 The Lead Generation Strategy is Defined by the Budget Allocated 22

2.5.9 Cost-Efficient but Information-Rich Lead Generation Strategies 23

2.5.10 The Revival of Potency as the Most Important Lead Criterion? 24

2.5.11 When has a LG Campaign Delivered Successfully? 27

References 31

Part II The Importance of Target Identification for Generating Successful Leads 35

3 “Ligandability” of Drug Targets: Assessment of Chemical Tractability via Experimental and In Silico Approaches 37
Udo Bauer and Alexander L. Breeze

3.1 Introduction 37

3.2 The Concept of Ligandability 39

3.2.1 General Characteristics of Ligandable Targets 39

3.3 The Intersection of Ligandability and Human Disease Target Space 40

3.3.1 Experimental Techniques for Assessing Target Ligandability 42

3.3.1.1 High-Throughput Screening and Subset/“Validation Set” Screening 43

3.3.1.2 Fragment Screening 44

3.4 Practical Examples of the Use of Fragment Screening for Ligandability Assessment 50

3.4.1 Chemical Tractability Assessment by in silico Approaches 54

3.4.1.1 Pocket-Finding Algorithms 54

3.4.1.2 Discrimination Functions and Validation Sets 55

3.4.1.3 Simulation-Based Methods for Identifying Interaction Potentials 56

3.5 Conclusions and Outlook 56

References 58

4 Chemistry-Driven Target Identification 63
Iván Cornella-Taracido, Ryan Hicks, Ola Engkvist, Adam Hendricks, Ronald Tomlinson, and M. Paola Castaldi

4.1 Introduction 63

4.2 Chemistry-Driven Target Discovery: Enabling Biology 65

4.2.1 Biological Samples 65

4.2.2 Cells Cultured in 2D 66

4.2.3 Cells Cultured in 3D, Organoids, and Tissues 67

4.2.4 Nonhuman Cells and Whole-Organism Screening 68

4.2.5 Functional Assays and Readouts 68

4.3 Chemistry for Target Discovery 71

4.3.1 Screening Deck Selection 71

4.3.2 Triaging and Prioritization of Chemical Matter 72

4.3.3 SAR Expansion and Probe Synthesis for Target Deconvolution 73

4.4 Small-Molecule Target Identification Techniques 75

4.4.1 In Silico Target Deconvolution 75

4.4.2 Biochemical Profiling 77

4.4.3 Target Deconvolution Correlational Tools 78

4.4.4 Subcellular Localization 79

4.4.5 Chemical Genetics 79

4.4.6 Affinity Chemical Proteomics 81

4.4.7 Target Corroboration 84

4.5 Conclusions 86

References 89

Part III Hit Generation Methods 93

5 Lead Generation Based on Compound Collection Screening 95
Dirk Weigelt and Ismet Dorange

5.1 Introduction 95

5.2 Screening of Existing Collections: the General Workflow 96

5.2.1 High-Throughput Screening 96

5.2.2 Medium-Throughput Screening: Selection Methods 98

5.3 Generation of New Screening Compounds 99

5.3.1 Collection Enhancement Programs 102

5.3.2 Library Design and Compound Selection 102

5.3.2.1 Number of Dimensions 103

5.3.2.2 Enumeration and Filtering 104

5.3.2.3 Layout 106

5.3.3 Focus on Synthetic Feasibility 107

5.3.3.1 Multicomponent Reactions 107

5.3.3.2 Click Chemistry 108

5.3.3.3 Diversity-oriented Synthesis 108

5.3.4 Structure-driven Approaches 109

5.3.4.1 Privileged Structures 110

5.3.4.2 Structure-driven Approaches Toward Unchartered Territory 112

5.3.5 Target Focus 114

5.3.5.1 Kinases 114

5.3.5.2 G-Protein-Coupled Receptors 115

5.3.5.3 Ion Channels 116

5.3.5.4 Protein–Protein Interactions 117

5.4 Other Concepts 117

5.4.1 Natural Products 118

5.4.2 DNA-Encoded Libraries 119

5.4.3 Spatially Addressed Libraries 120

5.4.4 On-bead Screening 120

5.4.5 Dynamic Combinatorial Chemistry 121

5.4.6 Cocktails and Mixtures 121

5.5 Summary and Outlook 122

References 123

6 Fragment-Based Lead Generation 133
Ivan V. Efremov and Daniel A. Erlanson

6.1 Introduction 133

6.2 Screening Methods 135

6.3 Hit Validation 137

6.4 Ligand Efficiency and Other Metrics 138

6.5 Hit Optimization 139

6.6 Fragment Growing 140

6.7 Fragment Linking 144

6.8 Protein–Protein Interactions 147

6.9 GPCRs 151

6.10 Computational Approaches 152

6.11 Conclusions 153

References 154

7 Rational Hit Generation 159
Bernd Wellenzohn and Alexander Weber

7.1 Introduction 159

7.2 Lead Generation: Transition State and Substrate Analogs 161

7.3 Hit Generation by Rational Library Design 165

7.4 Hit Generation by Virtual Screening 167

7.4.1 Structure-based VS in Enumerated Molecules 170

7.4.2 Ligand-based VS in Nonenumerated Virtual Chemical Spaces 171

7.5 Hit Generation by Scaffold Replacement Technologies 173

7.6 Hit Generation by Chemogenomics Approaches 174

7.7 Summary 178

References 178

8 Competitive Intelligence–based Lead Generation and Fast Follower Approaches 183
Yu Jiang, Ziping Liu, Jörg Holenz, and Hua Yang

8.1 Introduction 183

8.2 Competitive Intelligence-based Approach 185

8.2.1 Example A: A Case Study for the Hybrid Strategy 190

8.2.2 Example C: A Case Study for the Fused Strategy 192

8.2.3 Example C: A Case Study for the Fused Strategy 193

8.2.4 Example D: A Case Study for the Fused Strategy 196

8.2.5 Example E: A Case Study for the Chimera Strategy 197

8.3 Fast Follower Approach 201

8.3.1 Salfanilamide-based Fast Follower Approaches 202

8.3.2 Omeprazole-based Fast Follower Approaches 203

8.3.3 Rimonabant-based Fast Follower Approach 210

References 214

9 Selective Optimization of Side Activities: An Alternative and Promising Strategy for Lead Generation 221
Norbert Handler, Andrea Wolkerstorfer, and Helmut Buschmann

9.1 Introduction 221

9.1.1 Drug Selectivity and Unwanted or Desired Side Effects 222

9.2 Definition, Rational, and Concept of the SOSA Approach 223

9.2.1 Multiple Ligands and Polypharmacology 224

9.2.2 Safety and Bioavailability 225

9.3 Drugs in Other Drugs: Drug as Fragments 225

9.4 Drug Repositioning and Drug Repurposing 226

9.4.1 Old Drugs 226

9.5 The SOSA Approach and Analog Design 227

9.6 Patentability and Interference Risk of the SOSA Approach 230

9.6.1 Analogization, Optimization, and Isosterism 230

9.7 Case Studies and Examples 231

9.7.1 Sulfonamides 231

9.7.2 Morphine Analogs 232

9.7.3 Warfarin 232

9.7.4 Sildenafil (Viagra) 232

9.7.5 Thalidomide Analogs 233

9.7.6 Bupropion 234

9.7.7 Chlorpromazine 235

9.7.8 Chlorothiazide 235

9.7.9 Propranolol 235

9.7.10 Minaprine Analogs 236

9.7.11 Viloxazine Analogs 237

9.7.12 Methylation in the SOSA Strategy of Drug Design 237

9.7.13 Discovery of New Antiplasmodial Compounds 239

9.7.14 Drugs Acting on Central Nervous System Targets as Leads for Non-CNS Targets 241

9.7.15 Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator 242

9.7.16 Amiloride Analogs as Inhibitors of the Urokinase-type Plasminogen Activator 245

9.7.17 Flavonoids with an Oligopolysulfated Moiety: A New Class of Anticoagulant Agents 246

9.7.18 Clioquinol 249

9.8 Conclusions 251

References 252

10 Lead Generation for Challenging Targets 259
Jinqiao Wan, Dengfeng Dou, Hongmei Song, Xian-Hui Wu, Xuemin Cheng, and Jin Li

10.1 Introduction 259

10.2 DNA-Encoded Library Technology in Lead Generation 260

10.2.1 Background 260

10.2.2 DNA-Recorded Synthesis-Assisted Libraries 262

10.2.3 DNA-Templated Synthesis-Assisted Libraries 264

10.2.4 Encoded Self-Assembling Chemical Libraries 266

10.2.5 Summary and Perspective 267

10.3 Stapled Peptide 276

10.3.1 Background 276

10.3.2 Structure, Design, and Synthesis of Stapled Peptide 278

10.3.2.1 Stapled Peptide Structure 278

10.3.2.2 Stapled Peptide Design 280

10.3.2.3 Stapled Peptide Synthesis 282

10.3.3 Stapled Peptide Solution α-Helix Conversion Measurement 283

10.3.4 Stapled Peptide Affinity Evaluation and α-Helix Content Correlation 284

10.3.4.1 Surface Plasmon Resonance Binding Assays 284

10.3.4.2 Fluorescence Polarization Assay 284

10.3.4.3 Stapled Peptide Affinity and α-Helix Content Correlation 285

10.3.5 Stapled Peptide Permeability 286

10.3.6 Peptide Stability Assay 288

10.3.7 Outlook 288

10.4 Phenotypic Screening 289

10.4.1 Introduction 289

10.4.2 Basics for Establishing a Phenotypic Screen 291

10.4.2.1 Identify a “Druggable” Phenotype and the Type of Readout 291

10.4.2.2 Assay Design 291

10.4.2.3 Hit Selection and Secondary Assay 291

10.4.3 Typical Phenotypic Assays 292

10.4.3.1 Cell-Viability Assay 292

10.4.3.2 Fluorescent Imaging Plate Reader Technology 293

10.4.3.3 High-Content Screening 293

10.4.4 In Vitro Phenotypic Screening 293

10.4.4.1 Classic Phenotypic Screening 293

10.4.4.2 Patient-Derived Stem Cell in Drug Discovery 294

10.4.4.3 Phenotypic Screening on iPSC-Derived Disease Models 295

10.4.4.4 High-Content Cytotoxicity Screening by iPSC-Derived Hepatocytes 296

10.5 Summary 297

References 298

11 Collaborative Approaches to Lead Generation 307
Fabrizio Giordanetto, Anna Karawajczyk, and Graham Showell

11.1 Introduction 307

11.2 Creativity 308

11.3 Speed 308

11.4 Risk Sharing 308

11.5 Intellectual Property 309

11.6 Costs 309

11.7 Management 310

11.8 Lilly’s Open Innovation Drug Discovery 310

11.9 Molecular Library Program 312

11.10 EU Openscreen 314

11.11 European Lead Factory 315

11.12 Medicines for Malaria Venture 317

11.13 Open Source Malaria Project 320

11.14 Drugs for Neglected Diseases Initiative 320

11.15 Open Lab Foundation 321

11.16 Scientists Against Malaria 322

11.17 Open Source Drug Discovery 323

11.18 TB Alliance 323

11.19 Summary 324

References 325

Volume 68b

Dedication V

List of Contributors XXI

Part IV Converting Hits to Successful Leads 329

12 A Medicinal Chemistry Perspective on the Hit-to-Lead Phase in the Current Era of Drug Discovery 331
Dean G. Brown

12.1 Introduction 331

12.2 Active to Hit Processes 333

12.3 Target Potency: Energetics of Binding 336

12.4 Addressing Vast Chemical Space: HtL Strategies 345

12.5 Matched Pair Analysis 348

12.6 The Role of Hydrophobicity and HtL 351

12.7 Probing H-Bond Donors and Acceptors 353

12.8 Structure Based DD in HtL 356

12.9 Statistical Molecular Design 358

12.10 Hit to Lead is not Lead Optimization 359

12.11 Summary 362

References 363

13 Molecular Recognition and Its Importance for Fragment-Based Lead Generation and Hit-to-Lead 367
Thorsten Nowak

13.1 Introduction 367

13.2 Brief Summary of the Main Factors that Govern Molecular Interactions 368

13.3 Thermodynamics of Molecular Interactions and Impact on Hit Finding and Optimization 369

13.4 Enthalpy as a Key Decision Tool in Medicinal Chemistry 371

13.5 Importance of Enthalpic Interactions: Drivers of Selectivity and Specificity? 373

13.6 Fragment Screening Hit Optimization: Fragment Linking 374

13.7 Interstitial Waters and Their Usefulness: Case Studies on HSP-90 381

13.8 Fragments to Find Hot Spots in Binding Pockets 385

13.9 Nonclassical Hydrogen Bonds – Interactions of Halogen Atoms with Π-Systems and Carbonyl Groups: Factor Xa and Cathepsin L 386

13.10 Binding Mode Dependency of the Experimental Conditions and Chemical Framework of Ligand 390

13.11 Cooperativity in Binding: DAO or DAAO D-Amino Acid Oxidase 391

References 394

14 Affinity-Based Screening Methodologies and Their Application in the Hit-to-Lead Phase 401
Stefan Geschwindner

14.1 Introduction 401

14.2 Nuclear Magnetic Resonance Spectroscopy 402

14.3 Optical Biosensors: Surface Plasmon Resonance and Optical Waveguide Grating 404

14.4 Isothermal Titration Calorimetry 407

14.5 Thermal Shift Assay 411

14.6 Mass Spectrometry Approaches 412

14.7 Encoded Library Technologies 414

14.8 Emerging Technologies: Microscale Thermophoresis and Backscattering Interferometry 417

References 418

15 Predictive Methods in Lead Generation 425
Matthew D. Segall and Peter Hunt

15.1 Introduction 425

15.2 Compound Property Prediction 427

15.3 Multiparameter Optimization: Identifying High-Quality Compounds 430

15.3.1 Drug-like Properties 430

15.3.2 Filters 431

15.3.3 Desirability Functions and Probabilistic Scoring 432

15.3.4 Pareto Optimization 435

15.3.5 Example 436

15.4 De Novo Design: Guiding the Exploration of Novel Chemistry 439

15.4.1 Example Application 442

15.5 Selection: Balancing Quality with Diversity 443

15.6 Conclusions 445

References 447

16 Lead Quality 451
J. Willem M. Nissink, Sebastien Degorce, and Ken Page

16.1 Introduction 451

16.2 Properties in Drug Design 452

16.2.1 Primary Activity Assays 453

16.2.2 Physicochemical Properties 453

16.2.3 DMPK 454

16.2.4 Safety 454

16.2.5 Overall Profiles 456

16.3 Optimizing Properties: Useful Rules, Guides, and Simple Metrics for Early-Stage Projects 457

16.3.1 Rules for Potency: Ligand Efficiency Measures 457

16.3.2 Rules for Safety 462

16.3.3 Rules for DMPK and Mode of Administration: Early-Stage Structure-Based Profiling 464

16.3.3.1 Simple Design Rules for Good DMPK 464

16.3.3.2 Other DMPK Design Rules 465

16.3.4 Multiobjective Optimization 466

16.4 Predicted Dose to Man as a Measure of Early- and Late-Stage Lead Quality 467

16.4.1 Introduction 467

16.4.2 Description of Models and Data 469

16.4.3 Data Supporting Technique 471

16.4.3.1 Matching eD2M Doses with Normalized Observed Clinical Doses 472

16.4.3.2 Matching Cmax Values from eD2M and Clinical Studies 472

16.4.4 Flagging Potential Candidate Drugs Using eD2M 473

16.4.5 Determining Properties that Drive eD2M Predictions for a Series 474

16.5 Summary 480

References 481

Part V Hypothesis-driven Lead Optimization 487

17 The Strategies and Politics of Successful Design, Make, Test, and Analyze (DMTA) Cycles in Lead Generation 489
Steven S. Wesolowski and Dean G. Brown

17.1 DMTA Cycles: Perspectives from History 490

17.2 Test: What Assays, in What Order, and Why? 494

17.3 Additional Advice for “Test” Component of DMTA 496

17.4 Design: What to Make and Why? 496

17.5 Additional Advice for “Design” Component of DMTA 500

17.6 Make: Challenges and Strategies for Synthesis 501

17.7 Additional Advice for the “Make” Component of DMTA 502

17.8 Analyze: Making Sense of What’s Been Done and Formulating Sensible Plans for the Next Designs 502

17.9 Additional Advice for “Analyze” Component of DMTA 508

17.10 Results: Do Lead Optimization Teams Get What They Need? 508

References 509

Part VI Recent Lead Generation Success Stories 513

18 Lead Generation Paved the Way for the Discovery of a Novel H3 Inverse Agonist Clinical Candidate 515
Christophe Genicot and Laurent Provins

18.1 Introduction 515

18.2 Hit Identification 517

18.3 Lead Generation 521

18.3.1 Exploration of Oxazoline Substitution 523

18.3.2 Rigidification of Propoxy Linker 531

18.3.3 Oxazoline/Oxazole Surrogates: Lactams 533

18.3.4 Conclusions 536

18.4 Lead Optimization and Candidate Selection 537

18.5 Conclusions 543

Acknowledgments 544

References 544

19 Vorapaxar: From Lead Identification to FDA Approval 547
Samuel Chackalamannil and Mariappan Chelliah

19.1 Introduction 547

19.2 Background Information on Antiplatelet Agents 549

19.3 Thrombin Receptor (Protease-activated Receptor-1) Antagonists as a Novel Class of Antiplatelet Agents 550

19.4 Mechanism of Thrombin Receptor Activation 550

19.5 Preclinical Data Supporting the Antiplatelet Effect of Thrombin Receptor Antagonists 551

19.6 Himbacine-derived Thrombin Receptor Antagonists 552

19.6.1 Lead Identification 552

19.6.2 Lead Generation of Himbacine-derived Thrombin Receptor Antagonist Hit 553

19.6.2.1 Structure–Activity Relationship Studies 555

19.6.2.2 First-Generation Thrombin Receptor Antagonists 556

19.6.2.3 In vivo Metabolism of Himbacine Derivatives 558

19.6.2.4 Generation of Aryl Himbacine Leads 561

19.6.2.5 Second-Generation Leads that Incorporate Heteroatoms in the C-ring 562

19.6.2.6 Identification of nor-seco Himbacine Lead 564

19.6.3 Discovery of Vorapaxar (SCH 530348) 565

19.6.3.1 Clinical Studies of Vorapaxar 567

19.7 Conclusions 569

Abbreviations 570

Acknowledgments 570

References 571

20 Lead Generation Approaches Delivering Inhaled β2-Adrenoreceptor Agonist Drug Candidates 575
Michael Stocks and Lilian Alcaraz

20.1 Introduction 575

20.2 Lead Generation Exercises to Discover β2AR Agonist Clinical Candidates 577

20.3 AstraZeneca Lead Generation Exercises to Discover β2AR Agonist Clinical Candidates 587

20.4 Summary 593

References 593

21 GPR81 HTS Case Study 597
Eric Wellner and Ola Fjellström

21.1 General Remarks 597

21.2 The Target 598

21.3 Screening Cascade 599

21.4 Compound Selection (10 K Validation Set) 602

21.5 HTS 606

21.5.1 CSE 608

21.5.2 Single-Concentration Counterscreen 614

21.5.3 Clustering 615

21.5.4 Cluster Expansion and Nearest Neighbours 618

21.6 Hit Evaluation 618

21.6.1 Potency, Efficacy, and Curves 618

21.6.2 Binding Kinetics 621

21.6.3 Concentration–Response Counterscreen 622

21.6.4 Hit Assessment 622

21.6.4.1 Size and Lipophilicity Efficiency Assessment 622

21.6.4.2 Secondary Pharmacology Assessment 626

21.6.5 Secondary Screening Cascade and Hit Expansion 630

21.6.6 Biological Effect Assay 634

21.7 Alternative Lead Generation Strategies 638

21.7.1 Pepducins and Other Modified Peptides 641

21.8 Conclusions 645

References 646

22 Development of Influenza Virus Sialidase Inhibitors 651
Mauro Pascolutti, Robin J. Thomson, and Mark von Itzstein

22.1 Introduction 651

22.2 Targets for Anti-influenza Drug Development: Receptor Binding and Receptor Cleavage 652

22.2.1 Targeting Receptor Binding by Haemagglutinin 654

22.2.2 Targeting Receptor Destruction by Sialidase 655

22.2.3 Influenza Virus Sialidase: Structure and Mechanism 656

22.3 Development of Influenza Virus Sialidase Inhibitors 658

22.3.1 The Development of Zanamivir: Proof of Concept and First-in-Class Sialidase Inhibitor Drug 659

22.3.1.1 Template Selection 659

22.3.1.2 Structure-based Inhibitor Design 662

22.3.1.3 X-Ray Crystallographic Confirmation of Inhibitor Binding Mode 665

22.3.1.4 Selectivity for Influenza Virus Sialidase over Human Sialidases 666

22.3.1.5 Efficacy against Virus Replication 667

22.3.1.6 Mode of Administration of the Highly Polar Drug 667

22.3.1.7 Modifying the Presentation of Zanamivir: Prodrugs and Multivalency 668

22.3.2 Sialidase Inhibitor Development on Noncarbohydrate Scaffolds 671

22.3.2.1 A Sialidase Inhibitor Based on a Cyclohexene Scaffold: The Development of Oseltamivir 671

22.3.2.2 A Sialidase Inhibitor Based on a Cyclopentane Scaffold: The Development of Peramivir 673

22.3.3 Monitoring Resistance to Influenza Virus Sialidase Inhibitors 675

22.4 Summary and Future Directions 676

References 676

23 The Discovery of Cathepsin A Inhibitors: A Project-Adapted Fragment Approach Based on HTS Results 687
Sven Ruf, Christian Buning, Herman Schreuder, Wolfgang Linz, Dominik Linz, Hartmut Rütten, Georg Horstick, Markus Kohlmann, Katja Kroll, Klaus Wirth, and Thorsten Sadowski

23.1 General Background 687

23.2 Cathepsin A enzyme 687

23.2.1 Structural Biology and Catalytic Mechanism 687

23.2.2 Structural and Catalytic Functions of CatA 689

23.2.3 Tissue Distribution and Substrates 689

23.2.4 Natural Products and Synthetic Peptides as Inhibitors of CatA 690

23.3 CatA and the Link to Cardiovascular Disease 691

23.4 Lead Discovery 692

23.4.1 High-Throughput Screening and Data Analysis 692

23.4.2 Evaluation of Hit Series 693

23.4.2.1 Covalent Inhibitor Series 693

23.4.2.2 Malonamide Series 697

23.4.2.3 Pyrazolone Hit Series 698

23.4.3 Explorative Chemistry Delivers a Novel Lead Structure 699

23.4.3.1 Crystal Structure of 9b Bound to CatA 705

23.5 Lead Optimization 705

23.6 Toward an in vivo Proof of Concept 711

23.7 Summary and Conclusions 713

References 714

24 Lead Structure Discovery for Neglected Diseases: Product Development Partnerships Driving Drug Discovery 717
Jeremy N. Burrows and Takushi Kaneko

24.1 Introduction 717

24.2 Malaria and Medicines for Malaria Venture 719

24.3 Malaria Lead Generation Strategy 719

24.4 Hit Identification Strategies 722

24.5 Optimization of a Marketed Antimalarial Chemotype 723

24.6 Target-Based Approaches 723

24.7 Asexual Blood-Stage Phenotypic Screening 724

24.8 Whole-Cell Screening: Results 725

24.9 Repositioning of Clinical Candidates Developed for Other Indications 726

24.10 Case Studies 727

24.10.1 Dihydroorotate Dehydrogenase (DHODH) 727

24.10.2 Whole-Cell Screening 728

24.11 Screening for Malaria Eradication 729

24.12 Tuberculosis and the Global Alliance for Tuberculosis Drug Development (TB Alliance) 729

24.13 Target Product Profiles 730

24.14 TB Alliance’s Mission 730

24.15 Hit Generation Strategies for TB 732

24.16 Examples of Phenotypic Screens 733

24.17 Conclusions 741

References 741

25 A Fragmentation Enumeration Approach to Generating Novel Drug Leads 747
Pravin S. Iyer and Manoranjan Panda

25.1 Introduction 747

25.2 Principle 748

25.3 Research Methodology 748

25.3.1 Fragmentation 749

25.3.1.1 Origin of Parent Molecules 749

25.3.1.2 Cores and Daughters 749

25.3.1.3 Nonflat Cores 751

25.3.2 Intelligent Recombination and Enumeration 754

25.4 Evaluation 754

25.4.1 Preliminary Experimental Evaluation 755

25.4.2 In Silico Evaluation 755

25.4.3 Virtual Screening Using Enzyme–Ligand Docking 756

25.5 Summary 758

References 759

Index 761

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Author Information

Joerg Holenz is a trained organic and medicinal chemist and acquired his PhD in Germany on the synthesis of alkaloids as antimalarial agents. After leading the preclinical activities of the marketed analgesic Tapentadol (Grünenthal Pharmaceuticals GmbH), he headed the medicinal chemistry department of Barcelona-based Laboratorios Esteve. He then moved to AstraZeneca's CNS/ pain research unit in Sweden to head lead generation chemistry. In 2012, Joerg was selected to join AZ's newly formed 'virtual' neuroscience unit in Boston as director of discovery and preclinical sciences. As a project leader he is responsible for pioneering a novel concept of driving research and development projects via increased use of academic and industry collaborative networks. In his career, Joerg worked predominantly with peripheral and central targets in the pain and neuroscience disease areas. He has edited, authored or contributed to more than 45 publications, 50 patent applications and several books and book chapters.
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Reviews

"it is certainly the most comprehensive and up-to-date resource currently available on the topic"......."is an excellent resource for any scientist working in lead generation"......."This is a tribute to rational
drug discovery, which combined with very thorough up-to-date literature references and emphasis on emerging technologies, makes it a book we would readily suggest taking a look at" (Dr. Robert Webster, Dr. Nuria Ortega Hernandez Bayer Pharma AG, ChemMedChem, July 2017)
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