Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design, preparation, and selection of DNA-encoded dynamic libraries.

ABSTRACT: We report a method for the preparation and selection of DNA-encoded dynamic libraries (DEDLs). The library is composed of two sets of DNA-linked small molecules that are under dynamic exchange through DNA hybridization. Addition of the protein target shifted the equilibrium, favouring the assembly of high affinity bivalent binders. Notably, we introduced a novel locking mechanism to stop the dynamic exchange and "freeze" the equilibrium, thereby enabling downstream hit isolation and decoding by PCR amplification and DNA sequencing. Our DEDL approach has circumvented the limitation of library size and realized the analysis and selection of large dynamic libraries. In addition, this method also eliminates the requirement for modified and immobilized target proteins.

SUBMITTER: Li G

PROVIDER: S-EPMC5510007 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Design, preparation, and selection of DNA-encoded dynamic libraries.

Li Gang G Zheng Wenlu W Chen Zitian Z Zhou Yu Y Liu Yu Y Yang Junrui J Huang Yanyi Y Li Xiaoyu X

Chemical science 20150911 12

We report a method for the preparation and selection of DNA-encoded dynamic libraries (DEDLs). The library is composed of two sets of DNA-linked small molecules that are under dynamic exchange through DNA hybridization. Addition of the protein target shifted the equilibrium, favouring the assembly of high affinity bivalent binders. Notably, we introduced a novel locking mechanism to stop the dynamic exchange and "freeze" the equilibrium, thereby enabling downstream hit isolation and decoding by ...[more]

PMID: 28757982

Similar Datasets

Design, Construction, and Screening of Diversified Pyrimidine-Focused DNA-Encoded Libraries.

Project description:Pyrimidine is a ubiquitous component in natural products and approved drugs, providing an ideal modular scaffold for generating libraries with drug-like properties. DNA-encoded library technology introduces a novel library modality where each small molecule is covalently linked to a unique oligo tag. This technology offers the advantages of rapidly generating and interrogating large-scale libraries containing billions of members, substantially reducing the entry barrier to their use in both academia and the pharmaceutical industry. In this Letter, we describe the synthesis of three DNA-encoded libraries based on different functionalized pyrimidine cores featuring diversified chemoselectivity and regioselectivity. Preliminary screening of these DNA-encoded libraries against BRD4 identified compounds with nanomolar inhibition activities.

| S-EPMC10424316 | biostudies-literature

Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells.

Project description:We report the selection of DNA-encoded small molecule libraries against protein targets within the cytosol and on the surface of live cells. The approach relies on generation of a covalent linkage of the DNA to protein targets by affinity labeling. This cross-linking event enables subsequent copurification by a tag on the recombinant protein. To access targets within cells, a cyclic cell-penetrating peptide is appended to DNA-encoded libraries for delivery across the cell membrane. As this approach assesses binding of DELs to targets in live cells, it provides a strategy for selection of DELs against challenging targets that cannot be expressed and purified as active.

| S-EPMC7057806 | biostudies-literature

Navigating the DNA encoded libraries chemical space.

Project description:DNA-encoded library (DEL) technology is a novel ligand identification strategy that allows the synthesis and screening of unprecedented chemical diversity more efficiently than conventional methods. However, no reports have been published to systematically study how to increase the diversity and improve the molecular property space that can be covered with DEL. This report describes the development and application of eDESIGNER, an algorithm that comprehensively generates all possible library designs, enumerates and profiles samples from each library and evaluates them to select the libraries to be synthesized. This tool utilizes suitable on-DNA chemistries and available building blocks to design and identify libraries with a pre-defined molecular weight distribution and maximal diversity compared with compound collections from other sources.

| S-EPMC9814293 | biostudies-literature

Small-molecule discovery through DNA-encoded libraries.

Project description:The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal new ligands for a target of interest. Within the past 15 years, DNA-encoded library (DEL) technology has matured into a widely used platform for small-molecule discovery, yielding a wide variety of bioactive ligands for many therapeutically relevant targets. DELs offer many advantages compared with traditional screening methods, including efficiency of screening, easily multiplexed targets and library selections, minimized resources needed to evaluate an entire DEL and large library sizes. This Review provides accounts of recently described small molecules discovered from DELs, including their initial identification, optimization and validation of biological properties including suitability for clinical applications.

| S-EPMC10924799 | biostudies-literature

DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor.

Project description:Nature evolves molecular interaction networks through persistent perturbation and selection, in stark contrast to drug discovery, which evaluates candidates one at a time by screening. Here, nature's highly parallel ligand-target search paradigm is recapitulated in a screen of a DNA-encoded library (DEL; 73,728 ligands) against a library of RNA structures (4,096 targets). In total, the screen evaluated ∼300 million interactions and identified numerous bona fide ligand-RNA three-dimensional fold target pairs. One of the discovered ligands bound a 5'GAG/3'CCC internal loop that is present in primary microRNA-27a (pri-miR-27a), the oncogenic precursor of microRNA-27a. The DEL-derived pri-miR-27a ligand was cell active, potently and selectively inhibiting pri-miR-27a processing to reprogram gene expression and halt an otherwise invasive phenotype in triple-negative breast cancer cells. By exploiting evolutionary principles at the earliest stages of drug discovery, it is possible to identify high-affinity and selective target-ligand interactions and predict engagements in cells that short circuit disease pathways in preclinical disease models.

| S-EPMC8833215 | biostudies-literature

Building Block-Based Binding Predictions for DNA-Encoded Libraries.

Project description:DNA-encoded libraries (DELs) provide the means to make and screen millions of diverse compounds against a target of interest in a single experiment. However, despite producing large volumes of binding data at a relatively low cost, the DEL selection process is susceptible to noise, necessitating computational follow-up to increase signal-to-noise ratios. In this work, we present a set of informatics tools to employ data from prior DEL screen(s) to gain information about which building blocks are most likely to be productive when designing new DELs for the same target. We demonstrate that similar building blocks have similar probabilities of forming compounds that bind. We then build a model from the inference that the combined behavior of individual building blocks is predictive of whether an overall compound binds. We illustrate our approach on a set of three-cycle OpenDEL libraries screened against soluble epoxide hydrolase (sEH) and report performance of more than an order of magnitude greater than random guessing on a holdout set, demonstrating that our model can serve as a baseline for comparison against other machine learning models on DEL data. Lastly, we provide a discussion on how we believe this informatics workflow could be applied to benefit researchers in their specific DEL campaigns.

| S-EPMC10466377 | biostudies-literature

Universal encoding of next generation DNA-encoded chemical libraries.

Project description:DNA-encoded chemical libraries (DELs) are useful tools for the discovery of small molecule ligands to protein targets of pharmaceutical interest. Compared with single-pharmacophore DELs, dual-pharmacophore DELs simultaneously display two chemical moieties on both DNA strands, and allow for the construction of highly diverse and pure libraries, with a potential for targeting larger protein surfaces. Although methods for the encoding of simple, fragment-like dual-display libraries have been established, more complex libraries require a different encoding strategy. Here, we present a robust and convenient "large encoding design" (LED), which facilitates the PCR-amplification of multiple codes distributed among two partially complementary DNA strands. We experimentally implemented multiple coding regions and we compared the new DNA encoding scheme with previously reported dual-display DEL modalities in terms of amplifiability and performance in test selections against two target proteins. With the LED methodology in place, we foresee the construction and screening of DELs of unprecedented sizes and designs.

| S-EPMC8790773 | biostudies-literature

Diversified strategy for the synthesis of DNA-encoded oxindole libraries.

Project description:DNA-encoded library technology (DELT) employs DNA as a barcode to track the sequence of chemical reactions and enables the design and synthesis of libraries with billions of small molecules through combinatorial expansion. This powerful technology platform has been successfully demonstrated for hit identification and target validation for many types of diseases. As a highly integrated technology platform, DEL is capable of accelerating the translation of synthetic chemistry by using on-DNA compatible reactions or off-DNA scaffold synthesis. Herein, we report the development of a series of novel on-DNA transformations based on oxindole scaffolds for the design and synthesis of diversity-oriented DNA-encoded libraries for screening. Specifically, we have developed 1,3-dipolar cyclizations, cyclopropanations, ring-opening of reactions of aziridines and Claisen-Schmidt condensations to construct diverse oxindole derivatives. The majority of these transformations enable a diversity-oriented synthesis of DNA-encoded oxindole libraries which have been used in the successful hit identification for three protein targets. We have demonstrated that a diversified strategy for DEL synthesis could accelerate the application of synthetic chemistry for drug discovery.

| S-EPMC8179416 | biostudies-literature

Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries.

Project description:Bacterial resistance to β-lactam antibiotics is largely mediated by β-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. β-Lactamases that hydrolyze the last resort carbapenem class of β-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed to prevent β-lactamase-mediated hydrolysis and restore the efficacy of these antibiotics. However, there are few inhibitors available for problematic carbapenemases such as oxacillinase-48 (OXA-48). A DNA-encoded chemical library approach was used to rapidly screen for compounds that bind and potentially inhibit OXA-48. Using this approach, a hit compound, CDD-97, was identified with submicromolar potency (Ki = 0.53 ± 0.08 μM) against OXA-48. X-ray crystallography showed that CDD-97 binds noncovalently in the active site of OXA-48. Synthesis and testing of derivatives of CDD-97 revealed structure-activity relationships and informed the design of a compound with a 2-fold increase in potency. CDD-97, however, synergizes poorly with β-lactam antibiotics to inhibit the growth of bacteria expressing OXA-48 due to poor accumulation into E. coli. Despite the low in vivo activity, CDD-97 provides new insights into OXA-48 inhibition and demonstrates the potential of using DNA-encoded chemistry technology to rapidly identify β-lactamase binders and to study β-lactamase inhibition, leading to clinically useful inhibitors.

| S-EPMC7673237 | biostudies-literature

Scalable design of orthogonal DNA barcode libraries.

Project description:Orthogonal DNA barcode library design is an essential task in bioengineering. Here we present seqwalk, an efficient method for designing barcode libraries that satisfy a sequence symmetry minimization (SSM) heuristic for orthogonality, with theoretical guarantees of maximal or near-maximal library size under certain design constraints. Seqwalk encodes SSM constraints in a de Bruijn graph representation of sequence space, enabling the application of recent advances in discrete mathematics1 to the problem of orthogonal sequence design. We demonstrate the scalability of seqwalk by designing a library of >106 SSM-satisfying barcode sequences in less than 20 s on a standard laptop.

| S-EPMC11208133 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data