Searching for Molecular Solutions: Empirical Discovery and Its Future / Edition 1

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Overview

A comprehensive look at empirical approaches to molecular discovery, their relationships with rational design, and the future of both

Empirical methods of discovery, along with serendipitous and rational design approaches, have played an important role in human history. Searching for Molecular Solutions compares empirical discovery strategies for biologically useful molecules with serendipitous discovery and rational design, while also considering the strengths and limitations of empirical pathways to molecular discovery.

Logically arranged, this text examines the different modes of molecular discovery, empha-sizing the historical and ongoing importance of empirical strategies. Along with a broad overview of the subject matter, Searching for Molecular Solutions explores:

  • The differing modes of molecular discovery
  • Biological precedents for evolutionary approaches
  • Directed evolutionary methods and related areas
  • Enzyme evolution and design
  • Functional nucleic acid discovery
  • Antibodies and other recognition molecules
  • General aspects of molecular recognition
  • Small molecule discovery approaches
  • Rational molecular design
  • The interplay between empirical and rational strategies and their ongoing roles in the future of molecular discovery

Searching for Molecular Solutions covers several major areas of modern research, development, and practical applications of molecular sciences. This text offers empirical-rational principles of broad relevance to scientists, professionals, and students interested in general aspectsof molecular discovery, as well as the thought processes behind experimental approaches.

Note: CD-ROM/DVD and other supplementary materials are not included as part of eBook file.

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Editorial Reviews

From The Critics
Reviewer: Omer Iqbal, MD, FACC, FESC (Loyola University Medical Center)
Description: This useful book covers several major areas of modern research, development, practical applications of molecular science, and different modes of molecular discovery, emphasizing the historical and ongoing importance of empirical strategies.
Purpose: The aim is to make the case that finding useful molecules is far from simple and that empirical strategies will complement and even outperform rational approaches in many areas for the foreseeable future. The essential aim is to compare different modes of molecular discovery, with an emphasis on the historical and ongoing importance of empirical strategies.
Audience: The author intends this book for scientists, professionals, and students interested in the general aspects of molecular discovery, as well as the thought processes behind experimental approaches.
Features: The book begins with a very informative introduction to molecules. The 10 chapters deal with the differing modes of molecular discovery; biological precedents for evolutionary approaches; enzyme evolution and design; functional nucleic acid discovery; antibodies and other recognition molecules; general aspects of molecular recognition; small molecule discovery approaches; rational molecular design; the interplay between empirical and rational strategies; and their ongoing roles in the future of molecular discovery. The book is beautifully illustrated.
Assessment: This is a valuable resource that compares empirical discovery and rational design, while also considering the strengths and limitations of empirical pathways to molecular discovery. Scientists, professionals, and students interested in general aspects of molecular discovery will find this book extremely useful.
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Product Details

  • ISBN-13: 9780470146828
  • Publisher: Wiley, John & Sons, Incorporated
  • Publication date: 12/21/2009
  • Edition number: 1
  • Pages: 458
  • Product dimensions: 6.30 (w) x 9.40 (h) x 1.10 (d)

Meet the Author

Ian S. Dunn, PhD, is the Director of Research at Cytocure, LLC, in Beverly, Massachusetts. In keeping with the scope of this book, he has a diverse background in immunology, cell and molecular biology, and biotechnology. His current research focuses on antigen gene regulation in melanoma cells.
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Table of Contents

Acknowledgments xi

Introduction xni

1 If It Works, It Works: Pragmatic Molecular Discovery 1

Overview 1

Three Ways of Discovery 1

The Three Wise (Serendipitous) Men and Other Stories 1

An Empirical Fable 2

Productively Applying Empiricism 3

Screening Versus Selection 4

How to be a Librarian 6

Demon-strating the Power of Empirical Screening and Selection 11

Dreaming of Pandemonium: a Universal Molecular Space 13

Modes of Molecular Discovery 16

The Borderland of Rational Design 17

2 Empirical Miracles: Nature's Precedents for Empirical Solutions 22

Overview 22

Evolution Itself 22

Evolution: Natural and Artificial 25

To Opine on Design 26

Natural Evolution at Work 26

The Raw Materials: Diversity Enough and Time 26

GOD from Mutation 26

GOD from Recombination and Other Things 29

A Sexual Interlude 3

Doubling Up and Reassorting 34

Lateral Thinking 36

The Process: Old Ideas and Newer Wrinkles 39

The Marks of Lamarck? 39

Evolution by Order? 42

Orderly Beginnings 43

The Arrow of Complexity? 44

Drivers of Complexity 46

Complexity and Molecular Discovery 47

Molecules of Evolution and Design Boundaries 48

Evolving Proteins 49

Enzymatic Bounty 53

Combinatorial Catalysis and Its Helpers 54

Enzymes to the Limit 56

Absent by Irreducibility, or Lack of an Access Route? 57

Food for Evolutionary Thought 59

3 Evolution's Gift: Natural Somatic Diversification and Molecular Design 61

Overview 61

Immune Systems: a Biological Fundamental 61

The Selfish Scheme 62

The Xenobiotic "Immune System" and Beyond 63

Innately Selfish 64

How to Shoot Moving Targets 66

The Empirical Basis of theAdaptive Immune System 68

The Evolved GOD of the Adaptive Immune System 71

The T Cell Repertoire and Its Special GOD 75

The Range and Utility of Adaptive Immunity 80

Antibodies and Molecular Recognition in General 81

Selfishness Revisited 84

Antibody Libraries and Iterative Selection: Natural and Artificial 88

Iteratively Speaking 89

Such Selfish Systems Send Selfless Sermons: The Largesse of Immune Systems 91

GOD in the Brain and Its Extensions 91

Molecular Sensing 93

A Bittersweet Worldview 94

Smelling a Rat, and Many Other Things 97

Multirecogmtion 98

Messages in Biological Molecular Recognition and Empirical Design 99

4 Evolution While You Wait 103

Overview 103

Putting Evolution to Work 103

Levels of Selectable Replicators 104

The Scope and Implementation of Evolution as a Workhorse 105

God in the Laboratory 10

Mutations at Will 108

Sex for Biotechnologists 111

Artificial Evolution Becomes HOT 115

Evolution on the Laboratory Bench 117

Screen (Properly) and Ye Shall Find 117

A Highly Rational Empirical Process 120

Mutations and Libraries 124

Crossing the Valley of the Shadow of Low Fitness: Journeys across Molecular Spaces 127

Colorful Neutral Springboards 129

Punctuating Sequence Space, Naturally or Otherwise 130

The Power of Display 132

Show Me Your Coat: Phage on Display 135

Display Without Cells: Doing It In Vitro 137

Making Compartments 141

Test It, Replicate It, Evolve It 144

5 The Blind Protein Maker 145

Overview 145

Applying Natural Protein Evolution Principles 146

Productively Playing with Enzymes 147

Room for Improvement 147

Tougher Enzymes 148

Better Enzymes 152

Altered and Novel Enzymes 155

Enzymes from Scratch 159

De Novo Protein Design the Empirical Way 163

Return to the Fold 163

Alphabets and Patterning 168

Finding and Evolving Folds 172

De Novo Enzymes 173

Natural and Unnatural Acts 174

Unnatural Insertions 177

In Vitro opportunities 180

New Codes in Vivo 182

Unnatural Rewards and Limits 185

6 The Blind Shaper of Nucleic Acids 187

Overview 187

Functional Nucleic Acids and their Directed Evolution 187

Early Days 187

Protein-Free Enzymes 188

Finding Functional RNAs 190

Novel Ribozymes 193

Ribozyme Replication and Other Things 193

Comparisons with Proteins 196

Aiming for Stability 196

Recombination: Still Good for RNA? 198

Folding in Two Worlds 199

Working with the Ribozyme Repertoire 202

Calling for Cofactors 204

Alphabetic Acrobatics 205

Angling for Aptamers with Aptitude 208

DNA Can Do It Too 212

Natural Aptamers and Riboswitches 213

An Aptamerican Adventure 216

Allosteric Ribozymes and Aptamers 217

Payoffs from Functional Nucleic Acids 219

Aptamer Tools: Better than Antibodies? 219

Moving Aptamers Toward the Clinic 221

Extending the Functional Range of Nucleic Acids 223

Extended Alphabets 224

The Virtual Molecular Museum 224

Altered Backbones 227

The Best of Both Worlds? 232

7 Evolving and Creating Recognition Molecules

Overview 234

The Immune System in a Bottle and on a Leash 235

New Wrinkles on the Old Way to Antibodies 235

Antibodies and Libraries 239

The GOD of Small Things: Minimizing Antibodies 245

Antibodies as Catalysts 246

Alternatives to Antibodies 252

Other Protein Scaffolds for Molecular Recognition 253

Finding and Designing Proteins for Diversification 254

Molecular Imprinting: Making its Mark 258

Imprinting of Macromolecules 264

Comparing Recognition Alternatives 266

Generalizing to Foldamers 271

8 Molecules Small and Large 275

Overview 275

As Small as Possible, but No Smaller 276

Small and Natural, Small and Useful 276

How to Find New Drugs 282

Know Your NME 282

Aiming in the Right Direction 284

Druggable Struggles 285

High-throughput Put Through High Loops 286

Chemical Libraries and the GOD of Small Molecules 287

Generalities and the Natural Approach 287

Make Your Own Library 290

Frag-mental Inspiration 294

Self-Assembling Molecular Combinatorics 297

Codes for Small Molecules 299

Tag Team Technology: Encoded Combinatorial Chemistry 300

Marrying Chemistry and Biology with Tags 304

An Evolutionary Analogy 310

From Small to Large and Back Again 314

9 An Empirical-Rational Loop Forwards 315

Overview 315

Approaching Rational Design 315

Scope of Rational Design 315

Pathways to Rational Design 319

Quantum Chemistry and Rational Design 319

Small Molecules the Rational Way 320

Virtual Virtues 323

The De Novo Ultimate? 325

Proteins by the Book 326

Getting Folding Right 327

Making Rational Predictions 329

Making Rational Proteins 331

Designer Nucleic Acids 335

Systems, Pathways, and Networks 337

10 Exploring the Limits 343

Overview 343

The Limits of Rational Design 343

Rational Design and Determinism 344

Bootstrapping and Interplay 347

Reverse-engineering Biocomplexity for Design Insights 347

Time, Knowledge, and Molecules 349

Outer Boundaries 351

Patterns for the Future 353

Primordial Alphabet Soup 353

On Molecular Translations 356

Effectors and Replicators 358

The Universal Power of Combinatorics 360

A Kaleidoscopic View 362

Glossary 365

Bibliography 374

References in Figure Legends 440

Index 443

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