CHEMICAL CONSTITUTION AND PHYSIOLOGICAL ACTION
Introduction 1 References 4 I General Aspects 5 1 Target Family-directed Masterkeys in Chemogenomics 7 11 Introduction 7 12 Medicinal Chemistry-based Chemogenomics Approach 15 13 Densely Populated Target Families 16 14 Privileged Structures: A Brief Historical Assessment 18 15 Privileged Structures with Undesired Target Profiles 19 16 File Enrichment Strategies with Recurring Substructures 21 17 Recurring Structures Devoid of Target Family Correlations 22 18 Convergent Pharmacophores for Target-hopping 27 19 Target Family-directed Masterkey Concept 31 110 Conclusions and Perspective 36 References 38 2 Drug Discovery from Side Effects 43 21 A Historical Perspective: The Great Time of Serendipitous Observations 44 22 Clinical Observations of Side Effects 47 23 Privileged Structures Bind to Many Different Targets 51 24 Optimizing the Selectivity of Nonselective Lead Structures 55 25 Selective Optimization of Side Activities 59 26 Summary and Conclusions 65 References 65 3 The Value of Chemical Genetics in Drug Discovery 69 31 Introduction 69 32 Knowledge Management in Drug Discovery 70 33 Knowledge Gaps, Their Importance, and How to Address Them 71 34 Target Validation: The Foundation of Drug Discovery 72 35 Chemical Genetics – How Chemistry Can Contribute to Target Identification and Validation 72 36 Integration of Chemistry and Biology: Importance and Issues 75 37 Finding New Chemical Tools and Leads 75 38 Is Biological Selectivity an Illusion? 86 39 Synthesis of Chemical Genetics Libraries: New Organic Synthesis Approaches to the Discovery of Biological Activity 89 310 Information and Knowledge Management Issues 91 311 Annotation of Small Molecules 92 312 Summary 94 References 94 4 Structural Aspects of Binding Site Similarity: A 3D Upgrade for Chemogenomics 97 41 Introduction 97 411 Binding Sites: The Missing Link 97 412 Target Assessment 98 413 Lead Finding 99 414 Lead Optimization 100 42 Structural Biology of Binding Sites 101 421 Energetic, Thermodynamic, and Electrostatic Aspects 102 422 Functional Aspects 104 423 Specificity versus Function 105 424 Evolutionary Aspects 105 43 Methods for Identifying Binding Sites 106 431 Integrated Methods for the Prediction of Binding Sites 106 432 Sampling the Protein Surface 107 44 Methods for Detecting Binding Site Similarity 107 441 Searches for Specific Structural Motifs 108 442 General Methods for Searching Similar Structural Motifs 108 443 Similar Shape and Property Searches 111 45 Applications of Binding Site Analyses and Comparisons in Drug Design 114 451 Protein Kinases and Protein Phosphatases as Drug Targets 114 452 Relationships of Fold, Function, and Sequence Similarities 115 453 Druggability 117 454 Relationship between Ligand Similarity and Binding Site Similarity 118 455 Selectivity Issues 120 456 Caveats 123 457 Protein Flexibility 124 458 Ambiguities in Atom Type Assignment 125 459 Versatility of Interaction Types 127 4510 Crystallographic Packing Effects 128 46 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 51 Introduction 140 52 Molecular Information Systems for Targets and Ligands 141 53 Bioinformatics Discovery of Target Subfamilies with Conserved Molecular Recognition 145 54 Cheminformatics Discovery of Potential Ligands of Target Subfamilies with Conserved Molecular Recognition 149 55 Knowledge-based Combinatorial Library Design Strategies within Homogenous Target Subfamilies 155 56 Conclusions 161 References 162 6 Chemical Kinomics 167 61 Introduction 167 62 Chemical Biology: The Hope 169 63 Chemical Kinomics: A Target Gene Family Approach in Chemical Biology 169 631 Protein Kinase Inhibitor History 171 632 Chemical Kinomics: An Amenable Approach 172 6321 Examples of Traditional Chemical Genomics Using Kinase Inhibitors 172 6322 Forward Chemical Genomics Using a Kinase-biased Compound Library 174 6323 Chemical Validation 174 633 Orthogonal Chemical Genetics 176 6331 ASKAs: Analog-sensitive Kinase Alleles 176 6332 Cohen’s Inhibitor-insensitive p38 Mutants 178 6333 Active Inhibitor-insensitive Kinase Mutants (Orthogonal Protein Kinases) 179 634 Chemical Proteomics for Kinases: KinaTorTM 182 64 Conclusions 187 References 188 7 Structural Aspects of Kinases and Their Inhibitors 191 71 Introduction 191 72 Structural Aspects of Kinases 194 721 The General Structure of an Activated Kinase 194 722 Kinase Activation 197 73 Kinase Inhibition Principles 198 731 Substrate-competitive Inhibitors 198 732 ATP-competitive Inhibitors 200 733 Activation Inhibitors/Allosteric Modulators 200 734 Irreversible Inhibitors 203 74 Structural Aspects of Kinase Inhibitors 205 741 Kinase Inhibitor Scaffolds 205 742 Selectivity Issues 212 7421 The Selectivity Dogma 212 7422 The Gatekeeper 212 7423 Hinge-directed Selectivity 214 7424 Binding Region II-directed Selectivity 215 75 Outlook 216 References 216 8 A Chemical Genomics Approach for Ion Channel Modulators 221 81 Introduction 221 82 Structural Information on Ion Channels: Ion Channel Families 223 83 Lead-finding Strategies for Ion Channel Modulators 227 831 Ligand-based Lead Finding 228 832 Structure-based Lead Finding 230 84 Design of Ion Channel Focused Libraries: Chemical Genomics 233 841 Design Principles 233 842 Example: Building the Aventis Ion Channel Library 236 85 Conclusions 239 References 240 9 Phosphodiesterase Inhibitors: A Chemogenomic View 243 91 Introduction 243 92 PDE Isoenzymes and Subtypes 244 93 Potential Therapeutic Applications of PDE Inhibitors 247 94 Nonspecific PDE Inhibitors 247 95 Inhibitors of the cGMP-specific PDE5 and PDE6 249 951 Substrate-analogous PDE5 Inhibitors 249 952 Inhibitors Carrying a Chloromethoxybenzyl Substituent 253 953 Indole-type PDE5 Inhibitors 255 96 PDE6 Inhibitors 258 97 Inhibitors of cAMP-metabolizing PDE4 and PDE3 259 971 Dual PDE4/3 Inhibitors 268 972 PDE3 Inhibitors 269 98 Inhibitors of Other Phosphodiesterases 272 981 PDE1 272 982 PDE2 275 983 PDE7 277 984 Recently Discovered PDEs 8–11 278 99 Summary: A Chemogenomic View of PDE Inhibitors 280 References 281 10 Proteochemometrics: A Tool for Modeling the Molecular Interaction Space 289 101 Introduction 289 102 Definition and Principles of Proteochemometrics 290 103 Modeling and Interpretation of Interaction Space 292 104 Examples of Proteochemometric Modeling 295 1041 Proteochemometric Modeling of Chimeric MC Receptors Interacting with MSH Peptides 295 1042 Proteochemometric Modeling of ?1 Adrenoceptors Using z Scale Descriptors for Amino Acids 296 1043 Proteochemometric Modeling Using Wild-type Amine GPCRs 298 1044 Interaction of Organic Compounds with Melanocortin Receptor Subtypes 302 1045 Modeling of Interactions between ‘Proprietary Drug-like Compounds’ and ‘Proprietary Proteins’ 302 105 Large-scale Proteochemometrics 303 References 307 III Chemical Libraries 311 11 Some Principles Related to Chemogenomics in Compound Library and Template Design for GPCRs 313 111 Introduction 313 112 Diverse Libraries versus Targeted Libraries 314 113 Design of Targeted Libraries via Ligand-based Design 315 114 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 121 Introduction 325 122 Hard Filters 326 1221 Reducing the Number of False Positive Hits 326 1222 Lead-likeness, Drug-likeness 327 123 Soft Filters 329 1231 Prediction of Physicochemical Properties 329 1232 Prediction of ADME and Toxicity Properties 330 124 Prioritization of Chemotypes Based on Multivariate Profiling 331 125 Concluding Remarks 334 References 337 13 Navigation in Chemical Space: Ligand-based Design of Focused Compound Libraries 341 131 Defining Reference and Target 342 132 A Straightforward Approach: Similarity Searching 346 133 Fuzzy Pharmacophore Models 355 134 Fast Binary Classifiers for Library Shaping 358 1341 Artificial Neural Networks 360 1342 Support Vector Machines 361 1343 An Important Step: Data Scaling 362 1344 Application to Library Design 362 135 Mapping Chemical Space by Self-organizing Maps: A Pharmacophore Road Map 366 136 Concluding Remarks 371 References 372 14 Natural Product-derived Compound Libraries and Protein Structure Similarity as Guiding Principles for the Discovery of Drug Candidates 377 141 Introduction 377 142 Protein Folds and Protein Function 378 143 Implications for Library Design: Nature’s Structural Conservatism and Diversity 379 144 Development of Natural Product-based Inhibitors for Enzymes Belonging to the Same Family 381 1441 Nakijiquinone Derivatives as Selective Receptor Tyrosine Kinase Inhibitors 381 1442 Dysidiolide Derivatives as Cdc25 Phosphatase Inhibitors 383 145 Development of Natural Product-based Small-molecule Binders to Proteins with Low Sequence Homology yet Exhibiting the Same Fold 386 1451 Development of Leukotriene A4 Hydrolase Inhibitors 386 1452 Development of Sulfotransferase Inhibitors 389 1453 Development of Nuclear Hormone Receptor Modulators 393 146 Conclusion: A New Guiding Principle for Chemical Genomics? 399 References 401 15 Combinatorial Chemistry in the Age of Chemical Genomics 405 151 Introduction 405 152 Combinatorial Approaches to Natural Product Analogs 406 153 Diversity-oriented Synthesis of Natural-product-like Libraries 418 154 Conclusions 430 References 430