The theory, methods, and practices needed to generate and screen very large, high–quality, small molecule, and DNA–encoded libraries
Describing the development and practice of DNA–encoded library synthesis technology, this book expertly details an approach to drug discovery that offers an attractive addition to the portfolio of existing hit generation technologies such as high–throughput screening, structure–based drug discovery, and fragment–based screening. A Handbook for DNA–Encoded Chemistry is comprised of chapters summarizing practical methods, theoretical analysis, and reported applications. Important aspects of this technology, including DNA–compatible chemistry, DNA–encoded library synthesis, design of chemical genes, analytical methods for small molecule–DNA libraries, selection methods, hit identification, and DNA–directed chemistry are explored.
This book offers practicing chemists a variety of benefits:
- Guidance for understanding and applying DNA–encoded combinatorial chemistry to generate and screen novel chemical libraries
- A bridge to the interdisciplinary areas of DNA–encoded combinatorial chemistry synthetic and analytical chemistry, molecular biology, informatics, and biochemistry
- Instruction for medicinal and pharmaceutical chemists to efficiently broaden available chemical space for drug discovery
- Expert and up–to–date summary of reported literature for DNA–encoded and DNA–directed chemistry technology and methods
Despite many publications from laboratories specializing in DNA–encoded chemistry published since 1992, there has been no technical handbook offering this level of detail.
Introductory Comments xi
1 Just enough knowledge 1Agnieszka Kowalczyk
2 A brief history of the development of combinatorial chemistry and the emerging need for DNA–encoded chemistry 19Robert A. Goodnow, Jr.
3 A brief history of DNA–encoded chemistry 45Anthony D. Keefe
4 DN A–Compa tible Chemistry 67Kin–Chun Luk and Alexander Lee Satz
5 Foundations of a DNA–encoded library (DEL) 99Alexander Lee Satz
6 EXERCISES IN THE SYNTHESIS OF DNA–ENCODED LIBRARIES 123Steffen P. Creaser and Raksha A. Acharya
7 the dna tag: A Chemical gene designed for DNA–encoded libraries 153Andrew W. Fraley
8 Analytical challenges for DNA–encoded library systems 171George L. Perkins and G. John Langley
9 Informatics: Functionality and architecture for DNA–encoded library production and screening 201John A. Feinberg and Zhengwei Peng
10 Theoretical considerations of the application of DNA–encoded libraries to drug discovery 213Charles Wartchow
11 Begin with the End in Mind: The hit–to–lead process 231John Proudfoot
12 Enumeration and Visualization of Large Combinatorial Chemical Libraries 247Sung–Sau So
13 Screening Large Compound Collections 281Stephen P. Hale
14 Reported applications of DNA–encoded library chemistry 319Johannes Ottl
15 Dual–Pharmacophore DNA–Encoded Chemical Libraries 349Jörg Scheuermann and Dario Neri
16 Hit Identification and Hit Follow–up 357Yixin Zhang
17 Using DNA to Program Chemical Synthesis, Discover New Reactions, and Detect Ligand Binding 377Lynn M. McGregor and David R. Liu
18 the changing feasibility and economics of chemical diversity exploration with DNA–encoded combinatorial approaches 417Robert A. Goodnow, Jr.
19 Keeping the promise? An outlook on DNA chemical library technology 427Samu Melkko and Johannes Ottl