DNA-recorded Library

In this chapter, we will first discuss the basic principles of DNA-templated organic synthesis, as it is the mechanistic foundations for DNA-encoded libraries then we will discuss the progressive development of DNA-templated libraries and the evolution into a novel drug discovery tool. We will also discuss the DNA-recorded library, which also encodes library molecules with DNA but is conceptually different. These discussions will naturally involve specific drug discovery programs in which these libraries were applied and finally, we will discuss the outlook of DNA-eneoded libraries in the future of drug discovery. 

DNA-recorded library is another approach to encode small molecule libraries on DNA templates. Instead of preparing a template pool in which every library compound has already been encoded, in a DNA-recorded library initially all templates share an identical sequence, or even are simply one template. Usually, the chemical reactions on each template are encoded spatially such as the split-pool-split method i.e. the initial template pool is separated into several batches for discrete reactions with various building blocks. Before all the sub-pools are combined, an enzymatic tag is added to the template to record the synthesis. For every step, an additional tag is added. As a matter of fact, DNA-recorded library, similar to Harbury s DNA routing strategy discussed above, does not use DNA to template the reactants into proximity and to increase the effective molarity. 

DNA-recorded libraries exist in various formats and in the following sections we will discuss them based on the companies/research groups who invented them. 

DNA-linking carboxamide is found being exposed to solvent. Along with assayed binding potency of re-synthesized hit compounds, these data solidly validated the fidelity of the selection system enabled by the DNA tags used in a DNA-recorded library. 

This concept has been utilized by Neri s group in synthesizing DNA-recorded libraries called encoded self-assembling chemical (ESAC) libraries, and by Hamilton s group in constructing a library of bidentate fragments for binding to streptavidin. As a matter of fact, these libraries are not synthesized, but assembled by combinatorial DNA hybridization. 

Figure 8.22 Neri s DNA-recorded library synthesis scheme. The encoding is done by enzymatic extension. Reprinted, with permission, from Buller et al 2008 Elsevier.

In this approach, DNAs are tagged on small molecules and serve as barcodes to record both the structural information of the small molecules and the library information. DNA-recorded libraries, which consist of large numbers of encoded small molecules, have been generated in time- and cost-effective manner. Repeated cycles via a well-established procedure, known as spUt-and-pool synthesis strategy in combinatorial chemistry, ensure production of huge compound libraries with diversity. 

DNA-Recorded Synthesis Assisted Libraries Encoded Self-assembly chemical library... 

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