DNA-Encoded Chemical Libraries for the Discovery of MMP-3 Inhibitors

Scheuermann, Jörg; Dumelin, Christoph E.; Melkko, Samu; Zhang, Yixin; Mannocci, Luca; Jaggi, Madalina; Sobek, Jens; Neri, Dario

doi:10.1021/bc7004347

Cited by 90 publications

(76 citation statements)

References 33 publications

(50 reference statements)

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“…These fragments are then covalently coupled using a variety of linkers, and the resulting compounds are assayed without the DNA barcodes to discover linker architectures optimal for binding. Using ESAC, Neri and coworkers discovered higher-affinity inhibitors of trypsin [26] and MMP-3 [9]. …”

Section: In Vitro Selection Methods For Ligand Discoverymentioning

confidence: 99%

Novel selection methods for DNA-encoded chemical libraries

Chan

McGregor

Liu

2015

Current Opinion in Chemical Biology

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Driven by the need for new compounds to serve as biological probes and leads for therapeutic development and the growing accessibility of DNA technologies including high-throughput sequencing, many academic and industrial groups have begun to use DNA-encoded chemical libraries as a source of bioactive small molecules. In this review, we describe the technologies that have enabled the selection of compounds with desired activities from these libraries. These methods exploit the sensitivity of in vitro selection coupled with DNA amplification to overcome some of the limitations and costs associated with conventional screening methods. In addition, we highlight newer techniques with the potential to be applied to the high-throughput evaluation of DNA-encoded chemical libraries.

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Section: In Vitro Selection Methods For Ligand Discoverymentioning

confidence: 99%

Novel selection methods for DNA-encoded chemical libraries

Chan

McGregor

Liu

2015

Current Opinion in Chemical Biology

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“…58 Initially, panning a 550-membered DNA-encoded library against MMP3 identified a starting compound which was then used as a lead structure for the assembly of an ESAC library. Selection of the dual fragment library against MMP3 resulted in several combinations of synergistically binding molecules.…”

Section: Bioactive Synthetic Small Molecules Discovered From Dna-encomentioning

confidence: 99%

Small-molecule discovery from DNA-encoded chemical libraries

2011

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Researchers seeking to improve the efficiency and cost effectiveness of the bioactive small-molecule discovery process have recently embraced selection-based approaches, which in principle offer much higher throughput and simpler infrastructure requirements compared with traditional small-molecule screening methods. Since selection methods benefit greatly from an information-encoding molecule that can be readily amplified and decoded, several academic and industrial groups have turned to DNA as the basis for library encoding and, in some cases, library synthesis. The resulting DNA-encoded synthetic small-molecule libraries, integrated with the high sensitivity of PCR and the recent development of ultra high-throughput DNA sequencing technology, can be evaluated very rapidly for binding or bond formation with a target of interest while consuming minimal quantities of material and requiring only modest investments of time and equipment. In this review we describe the development of two classes of approaches for encoding chemical structures and reactivity with DNA: DNA-recorded library synthesis, in which encoding and library synthesis take place separately, and DNA-directed library synthesis, in which DNA both encodes and templates library synthesis. We also describe in vitro selection methods used to evaluate DNA-encoded libraries and summarize successful applications of these approaches to the discovery of bioactive small molecules and novel chemical reactivity.

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“…[66][67][68] Separately, this has also been creatively applied to study the binding of proteins to multivalent ligands and inhibitors, through directed self-assembly of the probes. 69,70 …”

Section: A Microarray Fabrication Approachesmentioning

confidence: 99%

Microarray-based enzyme profiling: Recent advances and applications (Review)

Uttamchandani

Moochhala

2010

Biointerphases

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Enzymes are an integral part of biological systems. They constitute a significant majority of all proteins expressed (an estimated 18%–29%) within eukaryotic genomes. It thus comes as no major surprise that enzymes have been implicated in many diseases and form the second largest group of drug targets, after receptors. Despite their involvement in a multitude of physiological processes, only a limited number of enzymes have thus far been well-characterized. Consequently, little is understood about the physiological roles, substrate specificity, and downstream targets of the vast majority of these important proteins. In order to facilitate the biological characterization of enzymes, as well as their adoption as drug targets, there is a need for global “-omics” solutions that bridge the gap in understanding these proteins and their interactions. Herein the authors showcase how microarray methods can be adopted to facilitate investigations into enzymes and their properties, in a high-throughput manner. They will focus on several major classes of enzymes, including kinases, phosphatases, and proteases. As a result of research efforts over the last decade, these groups of enzymes have become readily amenable to microarray-based profiling methods. The authors will also describe the specific design considerations that are required to develop the appropriate chemical tools and libraries to characterize each enzyme class. These include peptide substrates, activity-based probes, and chemical compound libraries, which may be rapidly assembled using efficient combinatorial synthesis or “click chemistry” strategies. Taken together, microarrays offer a powerful means to study, profile, and also discover potent small molecules with which to modulate enzyme activity.

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DNA-Encoded Chemical Libraries for the Discovery of MMP-3 Inhibitors

Cited by 90 publications

References 33 publications

Novel selection methods for DNA-encoded chemical libraries

Novel selection methods for DNA-encoded chemical libraries

Small-molecule discovery from DNA-encoded chemical libraries

Microarray-based enzyme profiling: Recent advances and applications (Review)

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