Chapter
1.5 Chemical Synthesis of DNA
1.6 Oligonucleotide Characterization
2 A Brief History
of the Development of
Combinatorial Chemistry
and the Emerging Ned for
DNA-Encoded Chemistry
2.3 Brief History of the Evolution of Combinatorial
Chemistry
2.3.1 Industrialization of Combinatorial Chemistry
2.3.2 Expectations of Purity, Identity, and Diversity:
Trying to Do More with a Parallel Action
2.4 Split-and-Pool Synthesis and the Encoding Solutions
2.4.1 The Potential of Split-and-Pool Synthesis
2.4.2 Addressing the Problem of Compound Identity
and Encoding: Early Attempts at Encoding Split-and-Pool
2.5 Encoding with Oligonucleotides
2.5.1 Limitations of the Combinatorial Chemistry Approach
That DNA-Encoded Libraries Begin to Address
2.5.2 Lessons Learned from the Experience of Combinatorial
Chemistry Applied to Drug Discovery
3 A Brief History of DNA -Encoded Chemistry
3.1 Before 1992: The Inspiration for DNA -Encoded Chemistry
3.2 1992–1995: The Conception of DNA -Encoded Chemistry
3.3 2001–2004: The Birth of Sequence-Directed DNA -Encoded Chemistry
3.4 2005–2012: The Further Development of Sequence-Directed DNA-Encoded Chemistry
3.5 2004–2012: Sequence-Recorded DNA-Encoded Chemistry
3.6 2012 and Beyond: The Future of DNA-Encoded Chemistry
4 DNA-Compatible Chemistry
4.1 Literature Examples of DNA-Compatible Chemistry and Their Use in Library Design
4.1.1 Practical Issues for DNA-Conjugated
Organic Transformations
4.1.2 General Methods for Reactions on DNA
4.1.3 Selected Examples of Methods for Reactions on DNA
4.1.4 Employing Known DNA-Compatible Chemistries to Construct DNA -Encoded Libraries (DELs)
4.2 Reactions That Have Potential for Use on DNA
4.2.1 Examples of Potential Libraries
4.2.2 Additional Potential Reactions
5 Foundations of a DNA-Encoded Library (DEL)
5.1 Introduction to the Requirements for Building Blocks
5.2 Practical Aspects of Building Block Acquisition
5.3 Simple Filters Used to Prioritize Building Block Acquisition
5.3.2 Stability and Structural Alerts
5.4 The Effect of Nested Libraries on Library Design and Building Block Acquisition
5.5 The Effect of High- MW Products on DEL Selections
5.6 Storage and Handling of Building Blocks
5.6.2 Preparing Building Block Tubes for Library Production
5.6.3 Informatic Sorting of Building Blocks
6 Exercises in the Synthesis of DNA-Encoded Libraries
6.4.4 Optical Density (OD) Measurements
6.5.1 Building Block Validation
6.8 Making Your First Million
6.8.1 Things You Will Need
6.9 Further Considerations
7 The DNA Tag: A Chemical Gene Designed for DNA-Encoded Libraries
7.2 Programmatic DNA-Encoded Libraries
7.2.4 DNA-Templated Chemistries
7.3 Postchemistry Manual Encoding
7.3.1 Postchemistry Self-Encoding
8 Analytical Challenges for DNA-Encoded Library Systems
8.2 Capillary Electrophoresis
8.3 High-Performance Liquid Chromatography (HPLC)
8.4 Mass Spectrometry of Nucleic Acids
8.5.2 Electrospray Ionization (ESI)
8.6.1 Quadrupole Mass Analyzers
8.6.2 Two-Dimensional and Three-Dimensional Quadrupole Ion Traps
8.6.3 Fourier Transform Ion Cyclotron Resonance Mass Spectrometry ( FT-ICR MS)
8.6.4 The Orbitrap™ or Electrostatic Trap
8.7 Hyphenation of LC and MS
8.8 Reported Analytical Method Conditions
9 Informatics: Functionality and Architecture for DNA-Encoded Library Production and Screening
9.2 An Informatics Perspective on the Workflow Associated with DNA -Encoded Libraries
9.3 Informatics Needs, Functionality, and Architecture
9.3.1 Library Idea Evaluation
9.3.2 Reaction Development and Reaction Building Block Validation
9.3.4 Affinity-Based Enrichment
9.3.6 Extraction of Assay Readout
9.3.7 Hit Analysis and Triage
9.4 Extraction of Assay Readout and Impact of Sequence Errors on Encoding Strategy
10 Theoretical Considerations of the Application of DNA-Encoded Libraries to Drug Discovery
10.2 The Drug Discovery Process
10.3 The Challenges of Emerging Targets
10.5 Biochemical Screening Methods and Campaigns
10.5.1 Factors Impacting Hit Identification in DNA-Encoded Library Screens
11 Begin with the End in Mind: The Hit-to-Lead Process
11.2 Historical Hit-to-Lead Process
11.2.1 Assess the Purity of the Hit Sample
11.2.2 Identify the Minimum Active Fragment
11.2.3 Enhance Selectivity versus Closely Related Molecular Targets
11.2.4 Separate Structure-Based from Property-Based Mechanisms of Action
11.3 Modern Hit-to-Lead Process and Implications for Library Follow-Up
11.3.1 (a), (b), (c) Compound Physicochemical Properties, Solubility, and Permeability
11.3.2 Metabolism Rates, Cytochrome P450 Enzyme Inhibition and Induction, and hERG Inhibition
11.3.3 Intellectual Property
11.3.5 Compound Promiscuity
11.4 The Importance of a High-Quality Screening Deck
12 Enumeration and Visualization of Large Combinatorial Chemical Libraries
12.2.1 Reagent Identification
12.2.3 Building Block Selection
12.2.4 Enumeration and Property Profiling
12.3 Chemical Space Comparison
12.3.1 Comparison of Exact Structures
12.3.2 Chemical Space Heat Map
12.3.3 Library Similarity Calculation
13 Screening Large Compound Collections
13.1 Affinity-Based Screening: A Chromatographic Approach
13.2 Screening Preparation
13.2.1 Screening Preparation: Target Considerations
13.2.3 Recombinant Targets
13.2.4 Screening Preparation: The Solid Phase
13.2.5 Screening Preparation: Encoded Control Compounds
13.2.6 Encoded Positive Control Compounds
13.2.7 Encoded Negative Control Compounds
13.2.8 Encoded Control Compound Evaluation
13.3.1 The Screen: Mock Considerations
13.3.2 The Screen: DNA-Only Screens
13.3.3 The Screen: Library Exposure to Target
13.3.4 The Screen: Removing Weakly Associated Compounds
13.3.5 The Screen: Recovery of Target-Associated Compounds
13.3.6 Decoding of Screening Output
13.5 Enrichment Data and Hit Identification
14 Reported Applications of DNA-Encoded Library Chemistry
14.1 Single-Pharmacophore Libraries
14.3 Applications of Single-Pharmacophore Split–Mix Libraries
14.4 DNA-Templated Synthesis ( DTS)
14.5 Dual-Pharmacophore Libraries
15 Dual-Pharmacophore DNA-Encoded Chemical Libraries
16 Hit Identification and Hit Follow-Up
16.1 Introduction: DNA-Encoded Chemical Libraries. Large Digitized Datasets in the Era of “Omics”
16.2 A Comparison of Protein/Peptide Display and DNA -Encoded Chemical Library in Hit Identification
16.3 Lessons from the First Selection and Decoding Experiments
16.4 Decoding before Deep Sequencing: From Digital to Analogue
16.4.1 A Weak Binding Moiety Can Contribute to Bidentate Interaction
16.4.2 Affinity Chromatography Provides a Ranking of Hit Compounds Superior to the Array Readout
16.5 Deep Sequencing in Decoding: From Analogue to Digital
16.5.1 The First Decoding Using Deep Sequencing
16.5.2 Selection with a DNA-Encoded Macrocycle Library
16.5.3 Large DNA-Encoded Chemical Libraries
16.6 Influence of Selection Conditions on Hit Identification
16.7 Hit Follow-Up: From On-DNA to Off-DNA
16.8 Challenges in Hit Identification
16.9.1 Direct Analysis of Binding in the Sequencing of DNA Tags
16.9.2 A Simple Database for DNA Encoding
17 Using DNA to Program Chemical Synthesis, Discover New Reactions, and Detect Ligand Binding
17.2 DNA-Recorded Synthesis
17.3 Noncovalent DNA-Assembled Libraries
17.4 Effective Molarity: A Basis for DNA-Programmed Reactivity
17.5 DNA-Programmed Synthesis
17.6 DNA-Templated Synthesis
17.7 Template Design for DNA-Encoded Libraries
17.8 Translation and Selection of a DNA-Templated Library of Peptide Macrocycles
17.9 In Vitro Selections for Protein Binding Using DNA-Encoded Chemical Libraries
17.10 Reaction Discovery Using DTS
17.11 PCR -Based Detection of Covalent and Noncovalent Bond-Forming Events
17.12 Other Solution-Phase Selections for Protein–Ligand Binding
18 the Changing Feasibility and Economics of Chemical Diversity Exploration with DNA-Encoded Combinatorial Approaches
18.1 An Outlook for Applications of DNA-Encoded Libraries
18.2 Future Innovation Guided by Potential Cost Advantage of DNA-Encoded Chemistry Library Technology
19 Keeping the Promise? An Outlook on DNA Chemical Library Technology
19.1 The Promise of DNA-Encoded Libraries
19.3 Selections Are Superior to Screening
A Handbook for DNA-Encoded Chemistry
：Theory and Applications for Exploring Chemical Space and Drug Discovery
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
