Gene Family Targeted Molecular Design

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ISBN: 9780470412893 | 0470412895
Cover: Hardcover
Copyright: 12/10/2008

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As research progresses and information continues to proliferate in the field of molecular design for therapeutic use, there is a need for a reference that brings current theory and proven practice together in a how-to volume. This reference guides scientists new to the field on how to design small molecules that interact with critical protein targets. The chapters condense useful material into a manageable format which is carefully organized and presented. It offers an essential resource for a variety of chemists in academia, and the biotech and pharmaceutical industries, as well as professionals in complementary fields.

Preface	p. xi
Contributors	p. xv
Drug Discoveries by Gene Family	p. 1
General Drug Discovery Components	p. 1
Further Reading for Expert Knowledge	p. 10
References	p. 13
G-Protein, Coupled Receptors	p. 15
Introduction	p. 15
GPCR Structure and function	p. 18
Subfamilies	p. 18
Structural Information and Homology Models	p. 22
Mechanisms of Receptor Modulation	p. 27
G-Protein Coupling and Assay Formats	p. 33
Challenges Facing the Area of GPCR Drug Design	p. 35
Hit Generation Strategies: Chemogenomics and Privileged Structures	p. 36
Case History: Calcitonin Gene-Related Peptide Receptor Antagonist (MK-0974, telecagepant)	p. 40
Case History: Mixed Dopamine/Serotonin Receptor Antagonist As An Atypical Anti-Psychotic	p. 43
Case History: Chemokine Receptor CCR5 Antagonist Maraviroc (Celsentri™)	p. 45
Case History: The Discovery of Cinacalcet (Sensipar (R)/Mimpara(R)), a CaSR-Positive Allosteric Modulator	p. 47
Conclusions and Outlook	p. 49
References	p. 50
Ion Channels Gene Family: Strategies for Discovering Ion Channel Drugs	p. 53
Introduction	p. 53
Ion Channel Subfamily Descriptions	p. 54
Voltage-Gated Ion Channels	p. 54
Inward Rectifier Potassium Channels	p. 55
Voltage-Gated Potassium Channels	p. 58
Calcium-Activated Potassium Channels	p. 61
Structure of Potassium Channels	p. 64
Criteria for Selection of Targets and Establishing Screens	p. 68
A Case Study in Ion Channel Drug Discovery	p. 70
Perspective on Ion Channels as Drug Targets	p. 77
References	p. 78
Integrins	p. 85
Introduction	p. 85
Integrin Inhibitor Discovery	p. 89
Cyclic Peptides	p. 91
Peptidomimetic Chemistry	p. 92
Preferred Peptidomimetic Fragments	p. 102
I-Domain Integrin Inhibitors	p. 103
Protein Structure-Based Design	p. 110
Challenges-Past and Future	p. 112
References	p. 113
Strategies for Discovering Kinase Drugs	p. 119
Introduction	p. 119
Protein Kinase Structural Features	p. 120
Generating and Optimizing Kinase Inhibitors	p. 124
ATP Binding Pocket	p. 124
Non-ATP Binding Pockets	p. 133
Establishing Screens for Understanding Kinase Activity and Selectivity	p. 135
Case Studies of Successful Kinase Drug Discovery	p. 140
References	p. 150
Protease-Directed Drug Discovery	p. 159
Introduction	p. 159
Aspartic Proteases	p. 162
HIV Protease Inhibitors	p. 164
Renin	p. 166
Metalloproteases	p. 168
Angiotensin-Coverting Enzyme	p. 168
Matrix Metalloproteases	p. 170
Serine Proteases	p. 175
Dipeptidyl Peptidase 4(DPP4)	p. 176
Trypsin-Like S1 Serine Proteases of the Coagulation Cascade	p. 179
Cysteine Proteases	p. 183
Cathepsin K	p. 184
Caspases	p. 188
Perspective on Proteases as Drug Targets	p. 190
References	p. 191
Small-Molecule Inhibitors of Protein-Protein Interactions: Challenges and Prospects	p. 199
Introduction	p. 199
Structure and Properties of PPI	p. 201
Constitutive versus Transient PPI	p. 201
Physicochemical Properties and Residue Propensities of PPI	p. 202
Binding Energetics and "Hotspots"	p. 204
Structural and Physicochemical Challenges to Inhibiting PPI with Small Molecules	p. 207
Key Role of Adaptivity at the Interface	p. 210
Constraints of "Drug-Like" Chemical Space	p. 212
Identifying Hits and Leads Against PPI Targets	p. 213
Fragment-Based Screening	p. 214
Validating and Optimizing Hits and Leads	p. 218
Assessing the Druggability of New PPI Targets	p. 225
References	p. 227
Transporter	p. 235
Introduction	p. 235
Methodologies in Transporter Drug Design	p. 239
Structure-Based Methods	p. 239
Ligand-Based Methods	p. 245
Therapeutic Transporter Targets in Drug Discovery	p. 248
Vacuolar ATPases	p. 248
Gastric (P-) ATPases	p. 251
Neurotransmitter Transporters as Drug Targets	p. 252
Transporters as Liability Targets	p. 256
P-glycoprotein	p. 259
Oatp1B1	p. 261
Application of Methods for Designing Interactions with Liability Targets	p. 262
Perspective	p. 267
References	p. 267
Nuclear Receptor Drug Discovery	p. 275
Introduction	p. 275
Nuclear Receptor Superfamily and Their Functions	p. 276
Agonism and Antagonism in Nuclear Receptor Functions	p. 279
AR Antagonists Effective Toward Mutated Receptors	p. 283
VDR Agonists and Antagonists	p. 286
Carboranes as Novel Hydrophobic Pharmacophores	p. 290
Medicinal Chemistry of Retinoid Nuclear Receptors	p. 293
Retinoid and Their Nuclear Receptors	p. 293
Retinobenzoic Acids	p. 300
RXR-Selective Ligands	p. 306
Clinical Application of Retinoids	p. 309
Perspective	p. 311
References	p. 312
Summary and Comparison of Molecules Designed to Modulate Druggable Targets in the Major Gene Families	p. 317
Target Class Concept	p. 317
Summary of the Unique Features of Each Target Class	p. 318
GPCR/7™	p. 318
Ion Channels	p. 320
Integrins	p. 322
Kinases	p. 323
Proteases	p. 324
Protein-Protein Interactions	p. 325
Transporters	p. 327
Nuclear Receptors	p. 328
Perspective	p. 330
References	p. 331
Appendix	p. 333
Index	p. 341
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Gene Family Targeted Molecular Design

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