Small-molecule discovery from DNA-encoded chemical libraries
- 14 June 2011
- journal article
- review article
- Published by Royal Society of Chemistry (RSC) in Chemical Society Reviews
- Vol. 40 (12), 5707-5717
- https://doi.org/10.1039/c1cs15076f
Abstract
Researchers seeking to improve the efficiency and cost effectiveness of the bioactive small-molecule discovery process have recently embraced selection-based approaches, which in principle offer much higher throughput and simpler infrastructure requirements compared with traditional small-molecule screening methods. Since selection methods benefit greatly from an information-encoding molecule that can be readily amplified and decoded, several academic and industrial groups have turned to DNA as the basis for library encoding and, in some cases, library synthesis. The resulting DNA-encoded synthetic small-molecule libraries, integrated with the high sensitivity of PCR and the recent development of ultra high-throughput DNA sequencing technology, can be evaluated very rapidly for binding or bond formation with a target of interest while consuming minimal quantities of material and requiring only modest investments of time and equipment. In this tutorial review we describe the development of two classes of approaches for encoding chemical structures and reactivity with DNA: DNA-recorded library synthesis, in which encoding and library synthesis take place separately, and DNA-directed library synthesis, in which DNA both encodes and templates library synthesis. We also describe in vitro selection methods used to evaluate DNA-encoded libraries and summarize successful applications of these approaches to the discovery of bioactive small molecules and novel chemical reactivity.Keywords
This publication has 55 references indexed in Scilit:
- A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery systemNature Chemistry, 2011
- Interaction-Dependent PCR: Identification of Ligand−Target Pairs from Libraries of Ligands and Libraries of Targets in a Single Solution-Phase ExperimentJournal of the American Chemical Society, 2010
- In Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase InhibitorsJournal of the American Chemical Society, 2010
- An in vitro translation, selection and amplification system for peptide nucleic acidsNature Chemical Biology, 2009
- Reactivity-Dependent PCR: Direct, Solution-Phase in Vitro Selection for Bond FormationJournal of the American Chemical Society, 2009
- Accurate whole human genome sequencing using reversible terminator chemistryNature, 2008
- Translation of DNA into a Library of 13 000 Synthetic Small-Molecule Macrocycles Suitable for in Vitro SelectionJournal of the American Chemical Society, 2008
- Development and Initial Application of a Hybridization-Independent, DNA-Encoded Reaction Discovery System Compatible with Organic SolventsJournal of the American Chemical Society, 2007
- Synthetic Ligands Discovered by in Vitro SelectionJournal of the American Chemical Society, 2007
- Exploring biology with small organic moleculesNature, 2004