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	Preface	XV
	A Personal Foreword	XVII
	List of Contributors	XXI
	Introduction Gerhard Müller and Hugo Kubinyi	1
	References	4

I	General Aspects	5

1	Target Family-directed Masterkeys in Chemogenomics Gerhard Müller	7
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 Hugo Kubinyi	43
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 Keith Russell and William F. Michne	69
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 Andreas Bergner and Judith Günther	97
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 Edgar Jacoby, Ansgar Schuffenhauer, and Pierre Acklin	139
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 Bert M. Klebl, Henrik Daub, and György Kéri	167
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 Rogier Buijsman	191
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 Karl-Heinz Baringhaus and Gerhard Hessler	221
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 Martin Hendrix and Christopher Kallus	243
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 Jarl E. S. Wikberg, Maris Lapinsh, and Peteris Prusis	289
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 Thomas R. Webb	313
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 Druglike Chemotypes Wolfgang Guba and Olivier Roche	325
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: Ligandbased Design of Focused Compound Libraries Gisbert Schneider and Petra Schneider	341
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 Marcus A. Koch and Herbert Waldmann	377
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 Reni Joseph and Prabhat Arya	405
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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