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DNA-Encoded Chemical Libraries
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DNA-Encoded Chemical Libraries

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 30592

Special Issue Editors

Dr. Raphael Franzini

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT, USA
Interests: DNA-encoded libraries; medicinal chemistry; chemical probes; bioorthogonal chemistry; oligonucleotides
Dr. Christopher Arico-Muendel

E-Mail Website
Guest Editor
GSK Discovery @ Cambridge, 200 Cambridge Park Drive, Cambridge, MA 02140, USA
Interests: drug discovery; DNA-encoded library technologies; bioorganic chemistry; medicinal chemistry; aptamers

Special Issue Information

Dear Colleagues,

Libraries of compounds encoded by DNA-sequence tags are rapidly gaining interest as advanced tools for the discovery of small-molecule hit compounds. Encoding pools of combinatorial compounds with DNA barcodes makes it possible to generate libraries of unprecedented size, which can be rapidly interrogated for protein binders using a simple affinity-selection protocol that requires only a fraction of the resources associated with conventional hit discovery methods. Due to the unique benefits of encoded libraries, they are being routinely used in pharmaceutical discovery efforts and are also being explored as disruptive technologies in other areas of chemistry and chemical biology. The objective of this Special Issue is to provide an overview of the ongoing efforts aimed at advancing encoded library technology. Areas of special interest include but are not limited to the development of reactions on DNA, encoding procedures, screening protocols including microfluidic technologies, and algorithms for the analysis of sequencing data. Reports of new libraries and the discovery of new molecules from screening such libraries are another focus of this Special Issue, as are novel applications, especially if the outcomes advance our quantitative understanding of affinity selection. Contributions relating to all types of encoded libraries are welcome, including libraries on beads, peptide libraries, libraries with unnatural backbones, and libraries designed for purposes other than drug discovery.

Dr. Raphael Franzini
Dr. Christopher Arico-Muendel
Guest Editors

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Keywords

  • DNA-encoded libraries
  • diversity screening
  • affinity selection
  • ELT
  • chemical biology
  • chemical probes
  • microfluidics

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Published Papers (4 papers)

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Research

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12 pages, 1681 KiB  
Communication
Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins
by Justin M. Rectenwald, Shiva Krishna Reddy Guduru, Zhao Dang, Leonard B. Collins, Yi-En Liao, Jacqueline L. Norris-Drouin, Stephanie H. Cholensky, Kyle W. Kaufmann, Scott M. Hammond, Dmitri B. Kireev, Stephen V. Frye and Kenneth H. Pearce
Molecules 2020, 25(4), 979; https://doi.org/10.3390/molecules25040979 - 22 Feb 2020
Cited by 14 | Viewed by 6744
Abstract
Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical [...] Read more.
Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains. Full article
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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19 pages, 3979 KiB  
Article
Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library
by Dongwook Kim, Yixing Sun, Dan Xie, Kyle E. Denton, Hao Chen, Hang Lin, Michael K. Wendt, Carol Beth Post and Casey J. Krusemark
Molecules 2019, 24(15), 2764; https://doi.org/10.3390/molecules24152764 - 30 Jul 2019
Cited by 14 | Viewed by 5160
Abstract
As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase [...] Read more.
As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase inhibitors with promise for improved specificity. Also, kinase activity detection approaches would benefit from substrates with improved activity and specificity. Here, we apply a substrate-mediated selection to a peptidomimetic DNA-encoded chemical library for enrichment of molecules that can be phosphorylated by the protein tyrosine kinase, c-Src. Several substrates were identified and characterized for activity. A lead compound (SrcDEL10) showed both the ability to serve as a substrate and to promote ATP hydrolysis by the kinase. In inhibition assays, compounds displayed IC50′s ranging from of 8–100 µM. NMR analysis of SrcDEL10 bound to the c-Src:ATP complex was conducted to characterize the binding mode. An ester derivative of the lead compound demonstrated cellular activity with inhibition of Src-dependent signaling in cell culture. Together, the results show the potential for substrate-mediated selections of DNA-encoded libraries to discover molecules with functions other than simple protein binding and offer a new discovery method for development of synthetic tyrosine kinase substrates. Full article
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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14 pages, 2335 KiB  
Article
Novel Nucleic Acid Binding Small Molecules Discovered Using DNA-Encoded Chemistry
by Alexander Litovchick, Xia Tian, Michael I. Monteiro, Kaitlyn M. Kennedy, Marie-Aude Guié, Paolo Centrella, Ying Zhang, Matthew A. Clark and Anthony D. Keefe
Molecules 2019, 24(10), 2026; https://doi.org/10.3390/molecules24102026 - 27 May 2019
Cited by 27 | Viewed by 6659
Abstract
Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to [...] Read more.
Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to discover binders to a panel of DNA targets. Here, we report the successful discovery of small molecules that specifically interacted with DNA G-quartets, which are stable structural motifs found in G-rich regions of genomic DNA, including in the promoter regions of oncogenes. For this study, we chose the G-quartet sequence found in the c-myc promoter as a primary target. Compounds enriched using affinity-mediated selection against this target demonstrated high-affinity binding and high specificity over DNA sequences not containing G-quartet motifs. These compounds demonstrated a moderate ability to discriminate between different G-quartet motifs and also demonstrated activity in a cell-based assay, suggesting direct target engagement in the cell. DNA-encoded chemical libraries and affinity-mediated selection are uniquely suited to discover binders to targets that have no inherent activity outside of a cellular context, and they may also be of utility in other nucleic acid structural motifs. Full article
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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Review

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22 pages, 1786 KiB  
Review
Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery
by Johannes Ottl, Lukas Leder, Jonas V. Schaefer and Christoph E. Dumelin
Molecules 2019, 24(8), 1629; https://doi.org/10.3390/molecules24081629 - 25 Apr 2019
Cited by 70 | Viewed by 10940
Abstract
The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands [...] Read more.
The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands for such targets. These binders facilitate drug discovery projects both as tools for target validation, structural elucidation and assay development as well as starting points for medicinal chemistry. Novartis internalized two complementing encoded library platforms to accelerate the initiation of its drug discovery programs. For the identification of low-molecular weight ligands, we apply DNA-encoded libraries. In addition, encoded peptide libraries are employed to identify cyclic peptides. This review discusses how we apply these two platforms in our research and why we consider it beneficial to run both pipelines in-house. Full article
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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