DNA-Encoded Libraries

Preface
Contents
A History of Selection-Based High-Throughput Screening Technologies for Hit Identification
1 1990-1991: Combinatorial Chemistry´s ``Big Bang´´
2 Exploring Encoded Library Strategies for Synthetic Libraries
3 High-Throughput Parallel and Combinatorial Synthesis (Without Encoding)
4 What Is a Hit Molecule?
5 Relationship Between Assay and Compound Purity Requirements
6 Target Agnostic Libraries
7 Focused Libraries
8 Encoding Techniques
9 Split and Pool Solid-Phase Synthesis of Libraries of Non-peptidic Oligomers
10 Summary of Pre-DEL Combinatorial Chemistry Efforts
11 The Maturation of Genetically Encoded Libraries
12 Target Agnostic Solution-Phase DECLs
13 Focused DECLs
14 Conclusion
References
Barcoding Strategies for the Synthesis of Genetically Encoded Chemical Libraries
1 Introduction: Encoding Molecules with Genetic Tags
2 Split-and-Pool Encoded Solution-Phase Combinatorial Chemistry
3 Split-and-Pool Encoded Solid-Phase Combinatorial Chemistry
4 PNA-Encoded Chemistry
5 Dual-Pharmacophore Encoding Strategies
6 Conversion from Double-Stranded to Single-Stranded Library Format
7 Dynamic Dual-Pharmacophore DEL Strategies
8 DNA-Templated Synthesis
9 DNA-Routing
10 DNA-Directed Chemistry: The ``yoctoReactor´´
11 Conclusion
References
Advancements in DEL-Compatible Chemical Reactions
1 Measuring DNA Damage
1.1 Introduction
1.2 Overview
1.3 Quantitative PCR
1.4 Characterisation of Chemical Reaction Compatibility
1.5 NGS to Measure DNA Damage
2 Modified DNA to Improve DNA Compatibility
2.1 Introduction
2.2 Overview
2.3 HexT
2.4 Chemical Modification
3 Non-covalent Reversible Solid Supports in DEL Synthesis
3.1 Introduction
3.2 Overview
3.3 Support Material
3.4 DNA Support Retention and Capacity
3.5 DNA Protection
3.6 New Chemistry Frontiers
4 Micellar Catalysis for DEL Synthesis
4.1 Introduction
4.2 Overview
4.3 Micelles Under the Microscope
4.4 Linker Choice for Micellar DEL Chemistry
5 Enzymatic Transformations for DEL Synthesis
5.1 Introduction
5.2 Overview
5.3 Enzyme Specificity
5.4 Product Analysis
5.5 Linker Importance on Selectivity
6 Electrochemistry and Radicals in a DEL Context
6.1 Introduction
6.2 Overview
6.3 Giese-Type Reaction
6.4 Electrochemistry in an Aqueous Environment
7 C-H Activation and DELs
7.1 Introduction
7.2 Overview
7.3 C(sp2)-H Activation
7.4 C(sp3)-H Activation
8 The Application of Photochemistry to DELs
8.1 Introduction
8.2 Overview
8.3 Impact of Oxygen on DEL Photoredox
8.4 Overcoming the Inconsistency of Photoredox Reactions for DELs
8.5 DNA Compatibility of LED Chemistry
8.6 Metallaphotoredox and DELs
9 Conclusion
References
Design Considerations in Constructing and Screening DNA-Encoded Libraries
1 Introduction
2 Synthesis Cycles, Library Topology, and Numeric Library Size
3 Choosing the Right Chemistry
3.1 Library Design: Non-scaffold Based
3.2 Scaffold-Based Design
4 Build Block (BB) Inclusivity
5 Atom Efficient Library Design
6 Escape from Flatland
7 Chemical Space Beyond Rule of Five
8 Practical Remarks and Considerations
9 Conclusions
References
Cheminformatics Approaches Aiding the Design and Selection of DNA-Encoded Libraries
1 Cheminformatics in DEL Technology Platform
2 Molecular Property Space Focused DEL Design
2.1 BB Collections and Initial Structural Filtering
2.2 Robust and Efficient Enumeration of DEL Products
2.3 Designing DELs of Diverse Products in a Focused Property Space
3 Rapid Decoding of DEL Selection Data
3.1 The Decoding Workflow
3.2 Data Noise and Uncertainty
4 DEL Selection Data Triage and Analysis
4.1 DEL Selection Conditions and Bio-Profiles
4.2 Identifying Bead Binders and Read Count Adjustment Using Blank Controls
4.3 Frequent Hitter Identification
4.4 DEL_DV Data Viewer
4.5 Recommended Triage Process for DEL Selection
5 Outlook and Perspectives
5.1 Structural Similarity Searching in DEL Libraries
5.2 Visualizing DEL Chemistry Space
5.3 Potential ML Applications for DEL Selection Analysis
References
Selection Strategies in DNA-Encoded Libraries
1 Introduction
2 Selection with Immobilized Libraries (Early Works)
3 Selection against Immobilized Targets
3.1 General Procedure
3.2 Selection for Covalent Inhibitors
3.3 Selection Data Analysis
4 Selection With In-Solution Targets
4.1 Target-Binding as the Prerequisite for Tag Amplification
4.2 Crosslinking-Based Methods
4.3 Kinetic Separation
4.4 DNA-Encoded Dynamic Library
5 Selection with Complex Biological Targets
5.1 Cell Lysates and Protein Complexes
5.2 Membrane Proteins
5.3 Intracellular Selections
5.4 Targeting Nucleic Acids
6 Functional DEL Selections
6.1 Ligand-Guided Selection to a Functionally Relevant Binding Site
6.2 Encoding the Outcome of the Biochemical Reaction
6.3 One-Bead, One-Compound (OBOC) DELs
7 Summary and Outlook
References
From DEL Selections to Validated Hits to Clinical Leads
1 DEL Selections
2 Data Analysis and Hit Triage
3 Hit Confirmation
4 Property Analysis of DEL-Derived Hits and Leads
5 Strategies in DEL Hit-to-Lead Optimization
5.1 Truncation of Inefficient Features
5.2 Potency and Physiochemical Property Optimization Guided by SBDD
5.3 Preorganization of Compound into Bound Conformation
6 DEL-Derived Clinical Candidates
7 Conclusions
References
A Perspective on 30 Years of DNA-Encoded Chemistry
1 Prologue
2 Praecis and the ``Birth´´ of DEL
3 GSK Steps in: Direct Select Becomes ELT
4 DEL Proliferates
5 HitGen Enters the Game
6 Adventures in Academia
7 DNA-Encoded Chemistry in 2022: Where Are We, and Some Thoughts on the Future
References