Protein‐Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

Jaegle, Mike; Wong, Ee Lin; Tauber, Carolin; Nawrotzky, Eric; Arkona, Christoph; Rademann, Jörg

doi:10.1002/anie.201610372

Cited by 65 publications

(67 citation statements)

References 160 publications

(404 reference statements)

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“…[23,62] A commonly applied method to analyze DCC experiments is the recording of HPLC-MS chromatograms of the libraries. We and Rademann and co-workers have reviewed the analytical methods used in protein-templated dynamic combinatorial chemistry to detect hit compounds.…”

Section: Analysis Of the Dclsmentioning

confidence: 99%

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

2019

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Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.

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Section: Analysis Of the Dclsmentioning

confidence: 99%

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

2019

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“…In in situ click chemistry, the reaction takes place between building blocks, whereas in the latter, thiol fragments covalently bind to the target. As tdDCC, both approaches employ the surface of a target protein as reaction vessel, which catalyzes the formation of covalent chemical bonds and leads to the evolution and identification of high‐affinity ligands …”

Section: Target‐directed Dynamic Combinatorial Chemistry: a Conceptuamentioning

confidence: 99%

Dynamic Combinatorial Chemistry: A New Methodology Comes of Age

Frei

Hevey

Ernst

2018

Chemistry A European J

105

101

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Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental set-ups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.

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“…Target‐guided synthesis (TGS) is a method that allows target enzymes to synthesize their own inhibitors . The inhibitors identified by TGS are expected to show strong activity and high target selectivity because they are synthesized by a specific reaction (catalytic reaction in the case of LSD1 inhibitors) and/or in specific pockets of a target enzyme.…”

Section: Drug Design For Lsd1‐selective Inhibitors Based On Target‐gumentioning

confidence: 99%

Drug Design Concepts for LSD1‐Selective Inhibitors

Ota

Suzuki

2018

The Chemical Record

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Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors.

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Protein‐Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

Cited by 65 publications

References 160 publications

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

Protein‐Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

Dynamic Combinatorial Chemistry: A New Methodology Comes of Age

Drug Design Concepts for LSD1‐Selective Inhibitors

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