Exploiting Chemical Diversity for Drug Discovery

, by Bartlett, Paul Alexander; Entzeroth, Michael

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ISBN: 9780854048427 | 0854048421
Cover: Hardcover
Copyright: 4/30/2006

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Conceptual and technological advances in chemistry and biology have transformed the drug discovery process. Evolutionary pressure among the diverse scientific and engineering disciplines that contribute to the identification of biologically active compounds has resulted in synergistic improvements at every step in the process. Exploiting Chemical Diversity for Drug Discovery encompasses the many components of this transformation and presents the current state-of-the-art of this critical endeavour. From the theoretical and operational considerations in generating a collection of compounds to screen, to the design and implementation of high-capacity and high-quality assays, this book provides a comprehensive overview of modern approaches to lead identification.Beginning with an introductory overview, subsequent chapters address topics that include the design of chemical libraries and methods for optimizing their diversity; automated and accelerated chemistry; high throughput assay design and detection techniques; and strategies for data analysis and property optimization. Written by experts in the field, both academic and industrial, and illustrated in full colour, this book provides an excellent overview for current practitioners and will also serve as a stimulating resource for future generations. Researchers in organic and medicinal chemistry, biological and pharmacological sciences, as well as those interested in allied computational and engineering disciplines, will value the comprehensive and up-to-date coverage.

Section 1 Operational Developments in Chemistry

Chapter 1 The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds

(30)

Steven V. Ley, Mark Ladlow and Emma Vickerstaffe

1 Introduction

(4)

2 PASP Synthesis Approaches to Biologically Active Compounds

(12)

2.1 Applications to the Synthesis of Commercial Drug Molecules

(3)

2.2 Applications of PASP to the Synthesis of Biologically Active Natural Products

(2)

2.3 PASP Synthesis in the Library Production of Biologically Active Small Molecules

(7)

3 Automated PASP Synthesis of Biologically Active Molecules

(9)

3.1 Stepwise Automation of PASP Synthesis in Batch Mode

(2)

3.2 Fully Automated PASP Synthesis of Drug-Like Molecules in Batch Mode

(2)

3.3 Flow Chemistry and Automation in the Synthesis of Drug-Like Molecules

(5)

4 Conclusion

(1)

References

(5)

Chapter 2 Accelerated Chemistry: Microwave, Sonochemical, and Fluorous Phase Techniques

(24)

Kristofer Olofsson, Peter Nilsson and Mats Larhed

1 Introduction

(1)

2 Microwave Enhanced Chemistry

(3)

2.1 General

(1)

2.2 Applications in Medicinal Chemistry

(2)

2.3 Applications in Solid-Phase Chemistry

(1)

3 Sonochemistry as a Means to Accelerate Synthesis

(3)

3.1 General

(1)

3.2 Organometallic Sonochemistry

(1)

3.3 Heterocyclic and Pericyclic Chemistry

(1)

3.4 Applications in Medicinal Chemistry

(1)

4 Fluorous Phase Techniques

(8)

4.1 General

(2)

4.2 Reagents, Linkers, and Scavengers

(2)

4.3 Fluorous Protecting Groups

(1)

4.4 Fluorous Mixture Synthesis

(1)

4.5 Peptides and Oligosaccharides

(1)

4.6 Fluorous Applications in High-Throughput Chemistry

(1)

4.7 Microwave-Enhanced Fluorous Chemistry

(2)

5 Conclusion

(1)

Acknowledgements

(1)

References

(9)

Section 2 Conceptual Advances in Synthesis: "Prospecting" — Design of Discovery Libraries and the Search for Hits

Chapter 3 Biosynthesis of "Unnatural" Natural Products

(34)

Yi Tang and Chaitan Khosla

1 Introduction

(4)

1.1 Polyketide Assembly

(2)

1.2 Three Major Classes of Polyketide Synthases

(1)

1.3 Methods for Engineered Biosynthesis

(1)

2 Type I Polyketide Synthases

(11)

2.1 Modular Architecture

(2)

2.2 The Erythromycin Synthase

(1)

2.3 Engineered Biosynthesis of Multimodular PKS Products

(1)

2.3.1 Domain Engineering

(1)

2.3.2 Module Engineering

(1)

2.3.3 Primer Unit Engineering and Precursor-Directed Biosynthesis

(2)

2.4 Multimodular PKSs that Exhibit Special Features

(1)

2.5 Fungal Type I PKSs

(2)

3 Type II Polyketide Synthases

(9)

3.1 Dissociated Architecture

(3)

3.2 Combinatorial Biosynthesis of Type II Polyketides

(1)

3.2.1 Chain-Length Variations

(1)

3.2.2 Mix and Match of Tailoring Enzymes

(1)

3.2.3 Primer Unit Modifications

(1)

3.2.4 Reshuffling of Downstream Tailoring Enzymes

(1)

4 Type III Polyketide Synthase

(4)

4.1 Type III PKS Consists of a Homodimeric Ketosynthase

(3)

4.2 Engineered Biosynthesis of Type III Polyketides

(1)

5 Conclusions

(1)

Acknowledgments

(1)

References

(5)

Chapter 4 Combinatorial Synthetic Design: The Balance of Novelty and Familiarity

(21)

A. Ganesan

1 Biological Macromolecules – Strength in Numbers

(21)

1.1 Congruence between Biological and Chemical Space

(1)

1.2 The Libraries are Exhaustive within the Defined Boundaries

(1)

1.3 Highly Optimized Synthesis Procedures were Available

(1)

2 Oligomer Synthesis – Improving on Mother Nature

(2)

3 Random, Discovery, or Prospecting Libraries the Quest for the Universal Scaffold

(1)

4 Privileged Scaffolds – Look Where the Light is Brightest

(1)

5 The Decoration or Synthesis of Novel Scaffolds Aid for the Underprivileged

(3)

6 Target Class Libraries – Diversity with a Purpose

100

(1)

7 Peptide and Nucleotide Libraries Redux

101

(1)

8 Lead Discovery or Drug Discovery – Size does Matter

102

(1)

9 Natural Product Scaffolds for Combinatorial Chemistry – Why Reinvent the Wheel?

103

(1)

10 From Natural Products to Natural Product-Like Libraries – Hubris or Progress?

104

(1)

11 Lead Discovery and Combinatorial Chemistry What have We Learned?

105

(2)

11.1 The Drug-Discovery Process cannot be Simplified to a Single Blueprint

106

(1)

11.2 Combinatorial Chemistry is an Extremely Powerful Technology

106

(1)

11.3 Combinatorial Chemistry is at its Best in Lead Optimization

107

(1)

11.4 Combinatorial Chemistry is about Making the Compounds that Fit Your Needs, not How They are Made

107

(1)

References

107

(5)

Chapter 5 Compound Collections: Acquisition, Annotation, and Access

112

(25)

Reg Richardson

1 Introduction

112

(1)

2 Commercial Offerings

113

(2)

3 Companies Providing Non-Proprietary, Non-Parallel Synthesised Libraries (Shared-Pool/'Collected Collections')

115

(2)

4 Companies Providing In-House Designed, Parallel Synthesised Libraries

117

(2)

5 Compound Selection and Database Filtering

119

(1)

6 Sub-structure Similarity/Dissimilarity

119

(1)

7 Pharmacophore Analysis

120

(4)

8 Annotation

124

(2)

9 Lipinski Rule-of-Five (LRoF)

126

(1)

10 Topological Polar Surface Area (tPSA) and Blood–Brain-Barrier Permeability (Log BB)

126

(2)

11 Solubility

128

(1)

12 Examples of the Use of Chemical Annotation and Pharmacophore-Based Lead-Hopping

129

(3)

13 Compound Acquisition

132

(2)

Acknowledgments

134

(1)

References

134

(3)

Chapter 6 Chemical Diversity: Definition and Quantification

137

(26)

Alan C. Gibbs and Dimitris K. Agrafiotis

1 Introduction

137

(1)

2 Diversity Metrics

138

(5)

2.1 Distance-Based Metrics

138

(2)

2.2 Cell-Base Diversity Metrics

140

(2)

2.3 Variance-Based Diversity Metrics

142

(1)

3 Molecular Description

143

(4)

3.1 Two-Dimensional Descriptors

143

(2)

3.2 Three-Dimensional Descriptors

145

(1)

3.3 Physicochemical and Electronic Descriptors

146

(1)

3.4 Descriptor Selection

146

(1)

4 Dimensionality Reduction

147

(4)

4.1 Principle Component Analysis

148

(1)

4.2 Singular-Value Decomposition

148

(1)

4.3 Factor Analysis (FA)

149

(1)

4.4 MultiDimensional Scaling

149

(1)

4.5 Stochastic Proximity Embedding

150

(1)

5 Subset Selection and Classification

151

(5)

5.1 Clustering

152

(1)

5.2 Partitioning Methods

153

(1)

5.3 Experimental Design

154

(1)

5.4 Reagent-Based Versus Product-Based Design

155

(1)

5.5 Random Versus Rational Design

155

(1)

6 Conclusion

156

(1)

Abbreviations

156

(1)

References

156

(7)

Section 3 Conceptual Advances in Synthesis: "Mining" – Turning a Hit into a Lead

Chapter 7 Focused Libraries: The Evolution in Strategy from Large-Diversity Libraries to the Focused Library Approach

163

(21)

Ruben Tommasi and Ivan Cornella

1 Introduction

163

(1)

2 A Synergistic, Multidisciplinary Approach to Library Conception

164

(3)

2.1 Improvements in Synthetic Methods

164

(1)

2.2 Impact of In Silico Tools for Library Design

165

(1)

2.3 Influence of Biology in Library Design

166

(1)

3 Library Design Concepts

167

(3)

3.1 Impact of Diversity on Library Design

167

(1)

3.2 Diversity-Oriented Synthesis in Prospecting Library Design

168

(1)

3.3 Target-Oriented Library Design

168

(2)

3.4 Focus on Drug-Like Libraries

170

(1)

4 Focused Libraries

170

(9)

4.1 Libraries Focused on Pharmacophore Models

170

(2)

4.2 Libraries Focused on Privileged Structures

172

(1)

4.3 Libraries Focused on Target Classes

172

(1)

4.3.1 GPCR-Targeted Libraries

173

(1)

4.3.2 Kinase-Targeted Libraries

174

(1)

4.3.3 Natural Product-Based Focused Libraries

174

(3)

4.4 Early Optimization or Hit-to-Lead Libraries

177

(2)

5 Summary

179

(1)

References

179

(5)

Chapter 8 Translating Peptides into Small Molecules

184

(19)

Gerd Hummel, Ulrich Reineke and Ulf Reimer

1 Peptides as Drugs: The Good, the Bad and the Ugly

184

(1)

2 Origin of Biologically Active Peptides

185

(1)

3 General Strategy for Translating Peptides into Small Molecules

186

(1)

4 Tailoring Peptide Sequences for their Translation into Small Molecules

186

(5)

5 Transformation of Peptide Ligands into Small Molecules using Computational Approaches

191

(7)

6 Conclusion

198

(1)

References

198

(5)

Section 4 Operational Developments in Screening and High Throughput Assays

Chapter 9 High-Density Plates, Microarrays, Microfluidics

203

(30)

Christof Fattinger and Gregor Dernick

1 Functional High-Density Well Plates for High-Throughput Assays

204

(11)

1.1 Sample Plates for Low-Volume High-Throughput Screening

205

(1)

1.2 High-Density Assay Plates for HTS and Multidimensional Compound Profiling

206

(2)

1.3 Technical, Biological, and Economical Limits for Assay Miniaturization in High-Density Plates

208

(2)

1.4 384-Microtube Plate for High-Throughput Retrieval of Compound Subsets

210

(1)

1.5 Sample Management for HTS and Multidimensional Compound Profiling

211

(4)

2 Parallel Liquid Handling of Low-Volume Samples

215

(8)

2.1 Pipetting and Dispensing in High-Density Plates

215

(4)

2.2 High-Throughput Aliquoting of the HTS Library

219

(3)

2.3 A Microfluidic Well Plate for High-Throughput Solid/Liquid Separations

222

(1)

3 Microarray Assays on Chips

223

(6)

3.1 Microchannel Assay: A New Generation of Miniaturized Multiplexed Bioassays

226

(3)

4 Prospects for Multiparameter Assays

229

(2)

Acknowledgment

231

(1)

References

231

(2)

Chapter 10 Fluorescence Technologies for the Investigation of Chemical Libraries

233

(14)

Eric Trinquet and Gérard Mathis

1 Introduction

233

(1)

2 Dissociation-Enhanced Lanthanide Fluoroimmunoas say

234

(2)

3 Enzyme Fragment Complementation

236

(1)

4 Fluorescence Polarization

236

(2)

5 Fluorescence Correlation Spectroscopy

238

(1)

6 Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen™)

238

(1)

7 Fluorescence Resonance Energy Transfer

239

(2)

8 Bioluminescence Resonance Energy Transfer

241

(1)

9 Homogeneous Time Resolved Fluorescence

241

(3)

10 Conclusion

244

(1)

References

245

(2)

Chapter 11 The Use of Genetically Engineered Cell-Based Assays in in-vitro Drug Discovery

247

(16)

Renate Schnitzer and Wolfgang Sommergruber

1 Introduction

247

(1)

2 Genetic Engineering for Cell-Based Assays

248

(2)

2.1 Expression Systems

248

(1)

2.2 Choice of Cell Line and Promoter

249

(1)

2.3 Chromosomal Integration Site

250

(1)

3 Reporter-Based Assays

250

(6)

3.1 Chloramphenicol Acetyl Transferase, Secreted Placental Alkaline Phosphatase, β-Galactosidase

251

(1)

3.2 Green Fluorescent Protein

252

(1)

3.3 Luciferase

252

(1)

3.4 β-Lactamase

253

(1)

3.5 Examples of Applications

254

(2)

4 Assays to Measure Intracellular Calcium

256

(1)

5 Assays to Monitor Protein–Protein Interactions

257

(2)

5.1 Bioluminescence Resonance Energy Transfer and Fluorescence Resonance Energy Transfer

257

(1)

5.2 Enzyme Complementation

258

(1)

6 Conclusions and Outlook

259

(1)

References

260

(3)

Chapter 12 NMR-Based Screening: A Powerful Tool in Fragment-Based Drug Discovery

263

(28)

Jochen Klages, Murray Coles and Horst Kessler

1 Introduction

263

(3)

2 NMR Screening: General Aspects

266

(2)

3 Ligand- vs. Target-Detected Methods

268

(1)

3.1 Sample Requirements

268

(1)

4 Incorporation of NMR into the Drug Discovery Process

269

(8)

4.1 Hit Finding

270

(1)

4.1.1 STD and WaterLOGSY

270

(1)

4.1.2 Libraries of 19F-Containing Ligands

272

(1)

4.2 Hit Validation

273

(1)

4.2.1 Chemical Shift Mapping

273

(1)

4.3 Hit Optimization

274

(1)

4.3.1 Chemical Shift Mapping

274

(1)

4.3.2 Competition-Based Screening

275

(1)

4.3.3 Paramagnetic Spin Labels

276

(1)

5 Representative Case Studies

277

(10)

5.1 Fluorine Screening

277

(5)

5.2 SAR-by-NMR

282

(3)

5.3 Saturation Transfer Double Difference

285

(2)

6 Conclusion

287

(1)

References

288

(3)

Chapter 13 Screening Chemical Microarrays: Methods and Applications

291

(24)

Pappanaicken R. Kumaresan and Kit S. Lam

1 Introduction

291

(4)

1.1 In situ Synthesis of Peptide and Non-Peptide Microarrays

293

(1)

1.2 Spotting of Pre-Synthesized Small Molecules and Peptides

293

(1)

1.3 Carbohydrate Microarrays

293

(1)

1.4 One-Bead-One-Compound Combinatorial Library Bead-Arrays

294

(1)

2 Screening of Chemical Microarrays

295

(5)

2.1 Labeling Methods

296

(1)

2.1.1 Fluorescence Method

296

(1)

2.1.2 Chemiluminescence Method

297

(1)

2.1.3 Radiolabeling Methods

297

(1)

2.1.4 Colorimetric Methods

297

(1)

2.2 Label-Free Optical and Mass Spectrometry Methods

298

(1)

2.2.1 Surface Plasmon Resonance

298

(1)

2.2.2 Oblique-Incidence Optical Reflectivity Difference Microscopy

298

(1)

2.2.3 Surface-Enhanced Laser Desorption/Ionization Mass Spectrometry

298

(1)

2.2.4 Atomic Force Microscopy

299

(1)

2.2.5 Fiber-Optic Bead Methods

299

(1)

2.2.6 Laser-Detection Methods

299

(1)

2.2.7 Electrochemical Biosensor Method

299

(1)

2.2.8 Cell-Based Assays

300

(1)

3 Applications of Chemical Microarrays

300

(6)

3.1 Basic Science Applications

301

(1)

3.1.1 Protein-Binding Arrays

301

(1)

3.1.2 Carbohydrate Microarrays for Cell Receptors

302

(1)

3.1.3 Cell-Signaling Arrays

302

(1)

3.1.4 Enzyme Substrate/Inhibitor Arrays

303

(1)

3.1.5 Chemical-Detection Arrays

303

(1)

3.2 Medical Applications

304

(1)

3.2.1 Diagnostic Arrays

304

(1)

3.2.2 Immunological Arrays

304

(1)

3.2.3 Cell-Binding Arrays

305

(1)

3.2.4 Drug-Discovery Arrays

305

(1)

4 Conclusion

306

(1)

Acknowledgments

306

(1)

References

307

(8)

Section 5 Conceptual Advances in Lead Evaluation: Screen Early and Often

Chapter 14 Screen/Counter-Screen: Early Assessment of Selectivity

315

(21)

Marlyn N. Banks, Litao Zhang and John G. Houston

1 Introduction

315

(2)

2 Approaches Used for Selection of Drug Candidates

317

(15)

2.1 Lead Evaluation and Liability Profiling

317

(1)

2.1.1 ADME Liability Profiling

318

(1)

2.1.2 The Lead Evaluation Process: Technologies and Methods

319

(4)

2.2 Specificity of Drug Candidates and the Construction of In Vitro Specificity Panels

323

(1)

2.2.1 Receptors

323

(1)

2.2.2 Protein Kinases

328

(1)

2.2.3 Ion Channels

331

(1)

3 Summary

332

(1)

References

332

(4)

Chapter 15 Concepts for In Vitro Profiling: Drug Activity, Selectivity and Liability

336

(28)

Michael B. Bolger, Robert Fraczkiewicz, Michael Entzeroth and Boyd Steere

1 Introduction

336

(3)

2 Physicochemical Parameters

339

(9)

2.1 Partition Coefficient

339

(1)

2.2 pKa

340

(3)

2.3 Solubility

343

(1)

2.3.1 Thermodynamic Solubility

343

(1)

2.3.2 To Buffer or not to Buffer

345

(3)

3 Permeability

348

(2)

4 Metabolism

350

(3)

5 Protein Binding

353

(1)

6 Toxicity

354

(3)

6.1 Cell Viability: MTS Assay for In Vitro Cytotoxicity

355

(1)

6.2 Membrane Damage: Release of LDH (Lactate Dehydrogenase)

355

(1)

6.3 Induction of Apoptosis: Caspase Activity

355

(1)

6.4 HERG Potassium Channel Interaction

355

(1)

6.5 Microarrays

356

(1)

6.6 Recent Approaches

357

(1)

7 Investigation of Compound Selectivity

357

(1)

8 Conclusion and Outlook

357

(3)

References

360

(4)

Chapter 16 In Silico Surrogates for In Vivo Properties: Profiling for ADME and Toxicological Behavior

364

(22)

Michael B. Bolger, Robert Fraczkiewicz and Boyd Steere

1 In Silico Surrogates for In Vivo Properties

364

(5)

1.1 Molecular Descriptor Generation

365

(1)

1.2 Modeling Methods

366

(1)

1.3 Multiple Linear Regression

366

(1)

1.4 Partial Least Squares

367

(1)

1.5 Artificial Neural Network

367

(1)

1.6 Support Vector Machines

368

(1)

2 Estimation of Biopharmaceutical Properties

369

(8)

2.1 Partition Coefficient

369

(1)

2.2 pKa

369

(5)

2.3 Permeability

374

(1)

2.4 Solubility

374

(2)

2.5 Protein Binding

376

(1)

3 Estimation of Pharmacokinetic Properties

377

(2)

3.1 Clearance

377

(1)

3.2 Volume of Distribution

377

(1)

3.3 Metabolism

378

(1)

4 Estimation of Toxicological Properties

379

(1)

5 Integration of Surrogate Data and Estimations with Physiological Simulation

380

(1)

References

381

(5)

Chapter 17 Uses of High Content Screening in Chemical Optimization

386

(19)

Francesca Casano, Zhuyin Li and Tina Garyantes

1 Introduction

386

(1)

2 When is HCS Used

387

(1)

3 HCS Systems

388

(2)

3.1 Limitations of HCS

388

(1)

3.2 How to Pick an HCS System

389

(1)

4 Examples Show the Power of HCS

390

(12)

4.1 Example 1: NF-kB Nuclear Translocation Assay (from Prelux)

390

(4)

4.2 Example 2: Characterization of Apoptosis Pathways Using High-Throughput Image-Based Assays (from Prelux)

394

(6)

4.3 Example 3: Gap Junction Inhibitors (from sanofi-aventis)

400

(2)

5 Summary

402

(2)

References

404

(1)

Subject Index

405

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Exploiting Chemical Diversity for Drug Discovery

Summary

Table of Contents

Supplemental Materials