Content
Preface XV
A Personal Foreword XVII
List of Contributors XXI
Introduction 1
Gerhard Müller and Hugo Kubinyi
References 4
I General Aspects 5
1 Target Family-directed Masterkeys in Chemogenomics 7
Gerhard Müller
1.1 Introduction 7
1.2 Medicinal Chemistry-based Chemogenomics Approach 15
1.3 Densely Populated Target Families 16
1.4 Privileged Structures: A Brief Historical Assessment 18
1.5 Privileged Structures with Undesired Target Profiles 19
1.6 File Enrichment Strategies with Recurring Substructures 21
1.7 Recurring Structures Devoid of Target Family Correlations 22
1.8 Convergent Pharmacophores for Target-hopping 27
1.9 Target Family-directed Masterkey Concept 31
1.10 Conclusions and Perspective 36
References 38
2 Drug Discovery from Side Effects 43
Hugo Kubinyi
2.1 A Historical Perspective: The Great Time of Serendipitous
Observations 44
2.2 Clinical Observations of Side Effects 47
2.3 Privileged Structures Bind to Many Different Targets 51
2.4 Optimizing the Selectivity of Nonselective Lead Structures 55
2.5 Selective Optimization of Side Activities 59
2.6 Summary and Conclusions 65
References 65
3 The Value of Chemical Genetics in Drug Discovery 69
Keith Russell and William F. Michne
3.1 Introduction 69
3.2 Knowledge Management in Drug Discovery 70
3.3 Knowledge Gaps, Their Importance, and How to Address Them 71
3.4 Target Validation: The Foundation of Drug Discovery 72
3.5 Chemical Genetics - How Chemistry Can Contribute to Target
Identification and Validation 72
3.6 Integration of Chemistry and Biology: Importance and Issues 75
3.7 Finding New Chemical Tools and Leads 75
3.8 Is Biological Selectivity an Illusion? 86
3.9 Synthesis of Chemical Genetics Libraries: New Organic Synthesis
Approaches to the Discovery of Biological Activity 89
3.10 Information and Knowledge Management Issues 91
3.11 Annotation of Small Molecules 92
3.12 Summary 94
References 94
4 Structural Aspects of Binding Site Similarity: A 3D Upgrade for
Chemogenomics 97
Andreas Bergner and Judith Günther
4.1 Introduction 97
4.1.1 Binding Sites: The Missing Link 97
4.1.2 Target Assessment 98
4.1.3 Lead Finding 99
4.1.4 Lead Optimization 100
4.2 Structural Biology of Binding Sites 101
4.2.1 Energetic, Thermodynamic, and Electrostatic Aspects 102
4.2.2 Functional Aspects 104
4.2.3 Specificity versus Function 105
4.2.4 Evolutionary Aspects 105
4.3 Methods for Identifying Binding Sites 106
4.3.1 Integrated Methods for the Prediction of Binding Sites 106
4.3.2 Sampling the Protein Surface 107
4.4 Methods for Detecting Binding Site Similarity 107
4.4.1 Searches for Specific Structural Motifs 108
4.4.2 General Methods for Searching Similar Structural Motifs 108
4.4.3 Similar Shape and Property Searches 111
4.5 Applications of Binding Site Analyses and Comparisons in Drug
Design 114
4.5.1 Protein Kinases and Protein Phosphatases as Drug Targets 114
4.5.2 Relationships of Fold, Function, and Sequence Similarities 115
4.5.3 Druggability 117
4.5.4 Relationship between Ligand Similarity and Binding Site
Similarity 118
4.5.5 Selectivity Issues 120
4.5.6 Caveats 123
4.5.7 Protein Flexibility 124
4.5.8 Ambiguities in Atom Type Assignment 125
4.5.9 Versatility of Interaction Types 127
4.5.10 Crystallographic Packing Effects 128
4.6 Summary and Outlook 129
References 132
II Target Families 137
5 The Contribution of Molecular Informatics to Chemogenomics.
Knowledge-based Discovery of Biological Targets and Chemical
Lead Compounds 139
Edgar Jacoby, Ansgar Schuffenhauer, and Pierre Acklin
5.1 Introduction 140
5.2 Molecular Information Systems for Targets and Ligands 141
5.3 Bioinformatics Discovery of Target Subfamilies with Conserved
Molecular Recognition 145
5.4 Cheminformatics Discovery of Potential Ligands of Target
Subfamilies with Conserved Molecular Recognition 149
5.5 Knowledge-based Combinatorial Library Design Strategies
within Homogenous Target Subfamilies 155
5.6 Conclusions 161
References 162
6 Chemical Kinomics 167
Bert M. Klebl, Henrik Daub, and György Kéri
6.1 Introduction 167
6.2 Chemical Biology: The Hope 169
6.3 Chemical Kinomics: A Target Gene Family Approach in Chemical
Biology 169
6.3.1 Protein Kinase Inhibitor History 171
6.3.2 Chemical Kinomics: An Amenable Approach 172
6.3.2.1 Examples of Traditional Chemical Genomics Using
Kinase Inhibitors 172
6.3.2.2 Forward Chemical Genomics Using a Kinase-biased
Compound Library 174
6.3.2.3 Chemical Validation 174
6.3.3 Orthogonal Chemical Genetics 176
6.3.3.1 ASKAs: Analog-sensitive Kinase Alleles 176
6.3.3.2 Cohen's Inhibitor-insensitive p38 Mutants 178
6.3.3.3 Active Inhibitor-insensitive Kinase Mutants
(Orthogonal Protein Kinases) 179
6.3.4 Chemical Proteomics for Kinases: KinaTorTM 182
6.4 Conclusions 187
References 188
7 Structural Aspects of Kinases and Their Inhibitors 191
Rogier Buijsman
7.1 Introduction 191
7.2 Structural Aspects of Kinases 194
7.2.1 The General Structure of an Activated Kinase 194
7.2.2 Kinase Activation 197
7.3 Kinase Inhibition Principles 198
7.3.1 Substrate-competitive Inhibitors 198
7.3.2 ATP-competitive Inhibitors 200
7.3.3 Activation Inhibitors/Allosteric Modulators 200
7.3.4 Irreversible Inhibitors 203
7.4 Structural Aspects of Kinase Inhibitors 205
7.4.1 Kinase Inhibitor Scaffolds 205
7.4.2 Selectivity Issues 212
7.4.2.1 The Selectivity Dogma 212
7.4.2.2 The Gatekeeper 212
7.4.2.3 Hinge-directed Selectivity 214
7.4.2.4 Binding Region II-directed Selectivity 215
7.5 Outlook 216
References 216
8 A Chemical Genomics Approach for Ion Channel Modulators 221
Karl-Heinz Baringhaus and Gerhard Hessler
8.1 Introduction 221
8.2 Structural Information on Ion Channels: Ion Channel Families 223
8.3 Lead-finding Strategies for Ion Channel Modulators 227
8.3.1 Ligand-based Lead Finding 228
8.3.2 Structure-based Lead Finding 230
8.4 Design of Ion Channel Focused Libraries: Chemical Genomics 233
8.4.1 Design Principles 233
8.4.2 Example: Building the Aventis Ion Channel Library 236
8.5 Conclusions 239
References 240
9 Phosphodiesterase Inhibitors: A Chemogenomic View 243
Martin Hendrix and Christopher Kallus
9.1 Introduction 243
9.2 PDE Isoenzymes and Subtypes 244
9.3 Potential Therapeutic Applications of PDE Inhibitors 247
9.4 Nonspecific PDE Inhibitors 247
9.5 Inhibitors of the cGMP-specific PDE5 and PDE6 249
9.5.1 Substrate-analogous PDE5 Inhibitors 249
9.5.2 Inhibitors Carrying a Chloromethoxybenzyl Substituent 253
9.5.3 Indole-type PDE5 Inhibitors 255
9.6 PDE6 Inhibitors 258
9.7 Inhibitors of cAMP-metabolizing PDE4 and PDE3 259
9.7.1 Dual PDE4/3 Inhibitors 268
9.7.2 PDE3 Inhibitors 269
9.8 Inhibitors of Other Phosphodiesterases 272
9.8.1 PDE1 272
9.8.2 PDE2 275
9.8.3 PDE7 277
9.8.4 Recently Discovered PDEs 8-11 278
9.9 Summary: A Chemogenomic View of PDE Inhibitors 280
References 281
10 Proteochemometrics: A Tool for Modeling the Molecular Interaction
Space 289
Jarl E. S. Wikberg, Maris Lapinsh, and Peteris Prusis
10.1 Introduction 289
10.2 Definition and Principles of Proteochemometrics 290
10.3 Modeling and Interpretation of Interaction Space 292
10.4 Examples of Proteochemometric Modeling 295
10.4.1 Proteochemometric Modeling of Chimeric MC Receptors
Interacting with MSH Peptides 295
10.4.2 Proteochemometric Modeling of ?1 Adrenoceptors Using
z Scale Descriptors for Amino Acids 296
10.4.3 Proteochemometric Modeling Using Wild-type Amine GPCRs 298
10.4.4 Interaction of Organic Compounds with Melanocortin
Receptor Subtypes 302
10.4.5 Modeling of Interactions between 'Proprietary Drug-like
Compounds' and 'Proprietary Proteins' 302
10.5 Large-scale Proteochemometrics 303
References 307
III Chemical Libraries 311
11 Some Principles Related to Chemogenomics in Compound Library and
Template Design for GPCRs 313
Thomas R. Webb
11.1 Introduction 313
11.2 Diverse Libraries versus Targeted Libraries 314
11.3 Design of Targeted Libraries via Ligand-based Design 315
11.4 Ligand-based Template Design for GPCR-targeted Libraries 315
References 320
12 Computational Filters in Lead Generation: Targeting Drug-like
Chemotypes 325
Wolfgang Guba and Olivier Roche
12.1 Introduction 325
12.2 Hard Filters 326
12.2.1 Reducing the Number of False Positive Hits 326
12.2.2 Lead-likeness, Drug-likeness 327
12.3 Soft Filters 329
12.3.1 Prediction of Physicochemical Properties 329
12.3.2 Prediction of ADME and Toxicity Properties 330
12.4 Prioritization of Chemotypes Based on Multivariate Profiling 331
12.5 Concluding Remarks 334
References 337
13 Navigation in Chemical Space: Ligand-based Design of Focused
Compound Libraries 341
Gisbert Schneider and Petra Schneider
13.1 Defining Reference and Target 342
13.2 A Straightforward Approach: Similarity Searching 346
13.3 Fuzzy Pharmacophore Models 355
13.4 Fast Binary Classifiers for Library Shaping 358
13.4.1 Artificial Neural Networks 360
13.4.2 Support Vector Machines 361
13.4.3 An Important Step: Data Scaling 362
13.4.4 Application to Library Design 362
13.5 Mapping Chemical Space by Self-organizing Maps: A Pharmacophore
Road Map 366
13.6 Concluding Remarks 371
References 372
14 Natural Product-derived Compound Libraries and Protein Structure
Similarity as Guiding Principles for the Discovery of Drug
Candidates 377
Marcus A. Koch and Herbert Waldmann
14.1 Introduction 377
14.2 Protein Folds and Protein Function 378
14.3 Implications for Library Design: Nature's Structural
Conservatism and Diversity 379
14.4 Development of Natural Product-based Inhibitors for
Enzymes Belonging to the Same Family 381
14.4.1 Nakijiquinone Derivatives as Selective Receptor
Tyrosine Kinase Inhibitors 381
14.4.2 Dysidiolide Derivatives as Cdc25 Phosphatase Inhibitors 383
14.5 Development of Natural Product-based Small-molecule Binders
to Proteins with Low Sequence Homology yet Exhibiting the Same
Fold 386
14.5.1 Development of Leukotriene A4 Hydrolase Inhibitors 386
14.5.2 Development of Sulfotransferase Inhibitors 389
14.5.3 Development of Nuclear Hormone Receptor Modulators 393
14.6 Conclusion: A New Guiding Principle for Chemical Genomics? 399
References 401
15 Combinatorial Chemistry in the Age of Chemical Genomics 405
Reni Joseph and Prabhat Arya
15.1 Introduction 405
15.2 Combinatorial Approaches to Natural Product Analogs 406
15.3 Diversity-oriented Synthesis of Natural-product-like
Libraries 418
15.4 Conclusions 430
References 430
Index 433
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