DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Abstract

The discovery of organic ligands that bind specifically to proteins is a central problem in chemistry, biology, and the biomedical sciences. The encoding of individual organic molecules with distinctive DNA tags, serving as amplifiable identification bar codes, allows the construction and screening of combinatorial libraries of unprecedented size, thus facilitating the discovery of ligands to many different protein targets. Fundamentally, one links powers of genetics and chemical synthesis. After the initial description of DNA-encoded chemical libraries in 1992, several experimental embodiments of the technology have been reduced to practice. This review provides a historical account of important milestones in the development of DNA-encoded chemical libraries, a survey of relevant ongoing research activities, and a glimpse into the future.

A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition

“…The observed fingerprint was observed when selections were performed at various concentrations of Tween-20, providing confidence about the reproducibility of the screening procedure[1h] [Supplementary Figure 6.1]. A plot of selection results, emphasizing sequence counts for various library members featuring the B101 building block, highlighted the preferential enrichment of compounds with linker A4 and with certain conserved structural features of C building blocks [Figure 4b,c].…”

“…The encoding of compounds with DNA tags, serving as amplifiable identification bar-codes, allows the facile construction and screening of large combinatorial chemical libraries[1]. The successful identification of binding molecules from DNA-encoded chemical libraries depends not only on the number and characteristics of the building blocks used for library construction, but also on library design[1].…”

“…The successful identification of binding molecules from DNA-encoded chemical libraries depends not only on the number and characteristics of the building blocks used for library construction, but also on library design[1]. We previously reported a DNA-encoded chemical library based on a conserved (S)-2,3-diaminopropanoic acid scaffold which had been combinatorially reacted with two sets of carboxylic acids that yielded nanomolar binders against various target proteins, including serum albumins and tankyrase-1[2].…”

A DNA‐Encoded Chemical Library Incorporating Elements of Natural Macrocycles

“…Te chnologies for screening pooled compound libraries offer an alternative,b ut come with the problem of accurate hit deconvolution after selection. [11] It took several years for this concept to become practical, [10,12] but today several library construction technologies have been demonstrated. Thus,after afunctional or binding selection, the structure of the best performers can be determined by standard DNAs equencing.…”

Eine DNA‐kodierte Molekülbibliothek mit Elementen natürlicher Makrocyclen

“…Diese "chamäleonartige" Eigenschaft ist wahrscheinlich der Grund, warum viele Makrocyclen trotz ihrer Grçße zellpermeabel sind. [11] Es dauerte zwar einige Jahre bis dieses Konzept praktikabel wurde, [10,12] aber es gibt heutzutage einige Te chnologien, um solche Bibliotheken herstellen zu kçnnen. In diesem Sinne wurde in letzter Zeit eine Reihe spannender,s owohl biologischer [8] als auch chemischer [3] Techniken entwickelt, um große Bibliotheken kodierter Makrocyclen herstellen zu kçnnen.…”