A Handbook for DNA–Encoded Chemistry: Theory and Applications for Exploring Chemical Space and Drug Discovery

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 chemistrysynthetic 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.

Preface vii Acknowledgments ix Introductory Comments xi Contributors xxiii 1 Just enough knowledge… 1 Agnieszka Kowalczyk 2 A brief history of the development of combinatorial chemistry and the emerging need for DNA–encoded chemistry 19 Robert A. Goodnow, Jr. 3 A brief history of DNA–encoded chemistry 45 Anthony D. Keefe 4 DN A–Compa tible Chemistry 67 Kin–Chun Luk and Alexander Lee Satz 5 Foundations of a DNA–encoded library (DEL) 99 Alexander Lee Satz 6 EXERCISES IN THE SYNTHESIS OF DNA–ENCODED LIBRARIES 123 Steffen P. Creaser and Raksha A. Acharya 7 the dna tag: A Chemical gene designed for DNA–encoded libraries 153 Andrew W. Fraley 8 Analytical challenges for DNA–encoded library systems 171 George L. Perkins and G. John Langley 9 Informatics: Functionality and architecture for DNA–encoded library production and screening 201 John A. Feinberg and Zhengwei Peng 10 Theoretical considerations of the application of DNA–encoded libraries to drug discovery 213 Charles Wartchow 11 Begin with the End in Mind: The hit–to–lead process 231 John Proudfoot 12 Enumeration and Visualization of Large Combinatorial Chemical Libraries 247 Sung–Sau So 13 Screening Large Compound Collections 281 Stephen P. Hale 14 Reported applications of DNA–encoded library chemistry 319 Johannes Ottl 15 Dual–Pharmacophore DNA–Encoded Chemical Libraries 349 Jörg Scheuermann and Dario Neri 16 Hit Identification and Hit Follow–up 357 Yixin Zhang 17 Using DNA to Program Chemical Synthesis, Discover New Reactions, and Detect Ligand Binding 377 Lynn M. McGregor and David R. Liu 18 the changing feasibility and economics of chemical diversity exploration with DNA–encoded combinatorial approaches 417 Robert A. Goodnow, Jr. 19 Keeping the promise? An outlook on DNA chemical library technology 427 Samu Melkko and Johannes Ottl Index 435

ROBERT A. GOODNOW, J R . is the Executive Director of the Chemistry Innovation Centre, Discovery Sciences at AstraZeneca and the Founder of GoodChem Consulting, LLC. He has extensive experience in drug discovery and chemistry technologies including carbohydrate, combinatorial, oligonucleotide, and analytical chemistry. Robert Goodnow has authored or coauthored nearly 100 publications and patents and has spoken extensively on the topics of drug lead finding and the outsourcing of drug discovery chemistry. He has lectured as an adjunct professor of medicinal chemistry.