Diversity-oriented synthesis as a tool to expand the chemical space of DNA-encoded libraries.
TL;DR: In this paper, a review of DNA-compatible complexity-generating reactions that can be applied for the generation of DNAencoded DOS libraries, including: (i) multicomponent reactions; (ii) C-H/C-X functionalization; (iii) tandem approaches; (iv) cycloadditions; (v) reactions introducing privileged elements.
About: This article is published in Bioorganic & Medicinal Chemistry.The article was published on 2021-05-15. It has received 12 citations till now. The article focuses on the topics: Chemical space.
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TL;DR: The recent progress in using DNA-encoded chemical libraries to interrogate complex biological targets and their potential to identify structures that elicit function or possess other useful properties are discussed.
31 citations
TL;DR: A visible light-promoted divergent synthesis of on-DNA benzoheterocycles from aldehydes is presented, demonstrating the feasibility of this approach in DNA-encoded chemical library construction.
14 citations
TL;DR: A sequential DNA-encoded synthesis strategy for polysubstituted pyrazoline heterocycles, which fuses a broad panel of aldehydes, aryl amines, and alkenes as building blocks, was presented in this paper.
11 citations
TL;DR: It is shown that dsD ELs could be efficiently converted to ssDELs and used for affinity-based selections either with purified proteins or on live cells.
Abstract: DNA-encoded library (DEL) is an efficient high-throughput screening technology platform in drug discovery and is also gaining momentum in academic research. Today, the majority of DELs are assembled and encoded with double-stranded DNA tags (dsDELs) and has been selected against numerous biological targets; however, dsDELs are not amendable to some of the recently developed selection methods, such as the cross-linking-based selection against immobilized targets and live-cell-based selections, which require DELs encoded with single-stranded DNAs (ssDELs). Herein, we present a simple method to convert dsDELs to ssDELs using exonuclease digestion without library redesign and resynthesis. We show that dsDELs could be efficiently converted to ssDELs and used for affinity-based selections either with purified proteins or on live cells.
7 citations
TL;DR: The DNA-encoded dynamic combinatorial libraries (DCLs) as mentioned in this paper have been widely adopted in the pharmaceutical industry and a number of clinical drug candidates have been identified from DEL selections.
Abstract: The DNA-encoded chemical library (DEL) has emerged as a powerful technology platform in drug discovery and is also gaining momentum in academic research. The rapid development of DNA-/DEL-compatible chemistries has greatly expanded the chemical space accessible to DELs. DEL technology has been widely adopted in the pharmaceutical industry and a number of clinical drug candidates have been identified from DEL selections. Recent innovations have combined DELs with other legacy and emerging techniques. Among them, the DNA-encoded dynamic library (DEDL) introduces DNA encoding into the classic dynamic combinatorial libraries (DCLs) and also integrates the principle of fragment-based drug discovery (FBDD), making DEDL a novel approach with distinct features from static DELs. In this Review, we provide a summary of the recently developed DEDL methods and their applications. Future developments in DEDLs are expected to extend the application scope of DELs to complex biological systems with unique ligand-discovery capabilities.
6 citations
References
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TL;DR: This Perspective highlights the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds.
Abstract: In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon–carbon and carbon–heteroatom bonds.
1,808 citations
TL;DR: The diversity of chemical synthesis and the power of genetics are linked to provide a powerful, versatile method for drug screening that can be amplified by replication and utilized for enrichment of the bound molecules by serial hybridization to a subset of the library.
Abstract: The diversity of chemical synthesis and the power of genetics are linked to provide a powerful, versatile method for drug screening. A process of alternating parallel combinatorial synthesis is used to encode individual members of a large library of chemicals with unique nucleotide sequences. After the chemical entity is bound to a target, the genetic tag can be amplified by replication and utilized for enrichment of the bound molecules by serial hybridization to a subset of the library. The nature of the chemical structure bound to the receptor is decoded by sequencing the nucleotide tag.
935 citations
TL;DR: An 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide is reported, assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection.
Abstract: Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
515 citations
TL;DR: DNA-templated organic synthesis (DTS) is emerging as a surprisingly general way to control the reactivity of synthetic molecules by using nature's effective-molarity-based approach.
Abstract: In contrast to the approach commonly taken by chemists, nature controls chemical reactivity by modulating the effective molarity of highly dilute reactants through macromolecule-templated synthesis. Nature's approach enables complex mixtures in a single solution to react with efficiencies and selectivities that cannot be achieved in conventional laboratory synthesis. DNA-templated organic synthesis (DTS) is emerging as a surprisingly general way to control the reactivity of synthetic molecules by using nature's effective-molarity-based approach. Recent developments have expanded the scope and capabilities of DTS from its origins as a model of prebiotic nucleic acid replication to its current ability to translate DNA sequences into complex small-molecule and polymer products of multistep organic synthesis. An understanding of fundamental principles underlying DTS has played an important role in these developments. Early applications of DTS include nucleic acid sensing, small-molecule discovery, and reaction discovery with the help of translation, selection, and amplification methods previously available only to biological molecules.
497 citations
TL;DR: A newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve challenging goals in synthetic chemistry is reviewed.
Abstract: The development of effective small-molecule probes and drugs entails at least three stages: 1) a discovery phase, often requiring the synthesis and screening of candidate compounds, 2) an optimization phase, requiring the synthesis and analysis of structural variants, 3) and a manufacturing phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in-house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small-molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning. Therefore, a challenge for synthetic chemistry is to develop a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases. Although this transformative chemistry remains elusive, progress is being made. Herein, we review a newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve these challenging goals.
490 citations