9780470551448

This book compares empirical discovery methods for biologically relevant molecules with serendipitous discovery and rational design, and highlights the general approach to empirical discovery and its advantanges/disadvantages. It provides a comprehensive and logical look at experimental methods for discovery of biologically relevant molecules, and includes sections on pragmatic molecular discovery, finding useful natural molecules, empirical methods, directed evolution, high-throughput synthesis and screening, rational molecular design, empirical versus rational design, and the limits of empirical methods.

Acknowledgements
Introduction
If it Works, it Works: Pragmatic Molecular Discovery
Overview
Three Ways of Discovery
The Three Wise (Serendipitous) Men and Other Stories
An Empirical Fable
Productively Applying Empiricism
Screening vs. Selection
How to be a Librarian
Demon-strating the Power of Empirical Screening
Dreaming of Pandemonium: a Universal Molecular Space
Molecular Discovery A La Mode
The Borderland of Rational Design
Empirical Miracles: Nature's Precedents for Empirical Solutions
Overview
Evolution Itself
Evolution - Natural and Artificial
To Opine on Design
Natural Evolution at Work
The Raw Materials: Diversity Enough and Time
GOD from Mutation
GOD from Recombination and Other Things
A Sexual Interlude
Doubling Up and Reassorting
Lateral Thinking
The Process: Old ideas and newer wrinkles
The Marks of Lamarck
Evolution by Order
Orderly Beginnings
The Arrow of Complexity
Drivers of Complexity
Complexity and Molecular Discovery
Molecules of Evolution and Design Boundaries
Evolving Proteins
Enzymatic Bounty
Combinatorial Catalysis and its Helpers
Enzymes to the Limit
Absent by Irreducibility, or lack of an Access Route
Food for Evolutionary Thought
Evolution's Gift: Natural Somatic Diversification and Molecular Design
Overview
Immune Systems: a Biological Fundamental
The Selfish Scheme
The Xenobiotic 'Immune System' and Beyond
Innately Selfish
How to Shoot Moving Targets
The Empirical Basis of the Adaptive Immune System
The Evolved GOD of the Adaptive Immune System
The T cell Repertoire and its special GOD
The Range and Utility of Adaptive Immunity
Antibodies and Molecular Recognition in General
Selfishness Revisited
Antibody Libraries and Iterative Selection - Natural and Artificial
Iteratively speaking
Such Selfish Systems Send Selfless Sermons - The Largesse of the Immune System
GOD in the Brain and its Extensions
Molecular Sensing
A Bittersweet Worldview
Smelling a Rat, and Many Other Things
Multi-recognition
Messages in Biological Molecular Recognition and Empirical Design
Evolution While You Wait
Overview
Putting Evolution to Work
Levels of Selectable Replicators
GOD in the Laboratory
Mutations at Will
Sex for Biotechnologists
Artificial Evolution Becomes HOT
Evolution on the Lab Bench
Screen (Properly) And Ye Shall Find
A Highly Rational Empirical Process
Mutations and Libraries
The Power of Display
Show Me Your Coat: Phage on Display
Display Without Cells: Doing it In Vitro
Making Compartments
Test it, Replicate it, Evolve it
The Blind Protein-Maker
Overview
Applying Natural Protein Evolution Principles
Productively Playing with Enzymes
Room for Improvement
Tougher Enzymes
Better Enzymes
Altered and Novel Enzymes
Enzymes from Scratch
De Novo Protein Design the Empirical Way
Return to the Fold
Alphabets and Patterning
Finding and Evolving Folds
De Novo Enzymes
Natural and Unnatural Acts
Unnatural Insertions
In vitro opportunities
New codes in vivo
Unnatural Rewards and Limits
The Blind Shaper of Nucleic Acids
Overview
Functional Nucleic Acids and their Directed Evolution
Early Days
Protein-free Enzymes
Finding functional RNAs
Novel Ribozymes
Ribozyme Replication and Other Things
Comparisons with Proteins
Aiming for Stability
Recombination: Still Good for RNA
Folding in Two Worlds
Working With the Ribozyme Repertoire
Calling for Cofactors
Alphabetic Acrobatics
Angling for Aptamers with Aptitude
DNA Can Do It Too
Natural Aptamers and Riboswitches
An Aptamerican Adventure
Allosteric Ribozymes and Aptamers
Pay-offs from Functional Nucleic Acids
Aptamer Tools: Better than Antibodies
Moving Aptamers Towards the Clinic
Extending the Functional Range of Nucleic Acids
Extended Alphabets
The Virtual Molecular Museum
Altered Backbones
The Best of Both Worlds
Evolving and Creating Recognition Molecules
Overview
The Immune System in a Bottle and on a Leash
New Wrinkles on the Old Way to Antibodies
Antibodies and Libraries
The GOD of Small Things - Minimizing Antibodies
Antibodies as Catalysts
Alternatives to Antibodies
Other Protein Scaffolds for Molecular Recognition
Finding and Designing Proteins for Diversification
Molecular Imprinting - Making its Mark
Imprinting of Macromolecules
Comparing Recognition Alternatives
Generalizing to Foldamers
Molecules Small and Large
Overview
As Small as Possible, but No Smaller
Small and Natural, Small and Useful
How to Find New Drugs
Know Your NME
Aiming in the Right Direction
Druggable Struggles
High-throughput Put Through High Loops
Chemical Libraries and the GOD of Small Molecules
Generalities, and the Natural Approach
Make Your Own Library
Frag-Mental Inspiration
Self-Assembling Molecular Combinatorics
Codes for Small Molecules
Tag Team Technology: Encoded Combinatorial Chemistry
Marrying Chemistry and Biology with Tags
An Evolutionary Analogy
From Small to Large and Back Again
An Empirical-Rational Loop Forwards
Overview
Approaching Rational Design
Scope of Rational Design
Pathways to Rational Design
Quantum Chemistry and Rational Design
Small Molecules the Rational Way
Virtual Virtues
The De Novo Ultimate
Proteins by the Book
Getting Folding Right
Making Rational Predictions
Making Rational Proteins
Designer Nucleic Acids
Systems, Pathways and Networks
Exploring the Limits
Overview
The Limits of Rational Design
Rational Design and Determinism
Bootstrapping and Interplay
Reverse-engineering Biocomplexity for Design Insights
Time, Knowledge, and Molecules
Outer Boundaries
Patterns for the Future
Primordial Alphabet Soup
On Molecular Translations
Effectors and Replicators
The Universal Power of Combinatorics
A Kaleidoscopic View
Glossary
Bibliography
Index
Table of Contents provided by Publisher. All Rights Reserved.

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Searching for Molecular Solutions : Empirical Discovery and Its Future

0470551445

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