Detection of Ligands from a Dynamic Combinatorial Library by X‐ray Crystallography

Congreve, Miles; Davis, Deborah; Devine, Lindsay A.; Granata, Cesare; O’Reilly, Marc; Wyatt, Paul G.; Jhoti, Harren

doi:10.1002/anie.200351951

Cited by 98 publications

(72 citation statements)

References 28 publications

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“…[5] The use of X-ray and NMR techniques has been extended beyond pure structural characterization to new approaches for structure-based lead discovery. [6,7] Both NMR- [8] and X-raybased [9] screening of mixtures have been introduced in pharmaceutical research. In general, crystallography has the advantage over NMR techniques for the definition of ligand-binding sites.…”

mentioning

confidence: 99%

A Potent HIV Protease Inhibitor Identified in an Epimeric Mixture by High‐Resolution Protein Crystallography

et al. 2006

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mentioning

confidence: 99%

A Potent HIV Protease Inhibitor Identified in an Epimeric Mixture by High‐Resolution Protein Crystallography

et al. 2006

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“…Instead, increased amounts of the highest affinity library members are detected with established analytical methods like HPLC, mass spectrometry (MS), NMR spectroscopy or even X-ray crystallography. 9,10 It may be more advantageous for the library to amplify many members with moderate affinities than just a few with high affinities. This behaviour reflects the complex nature of DCLs consisted of members interconnected through a set of equilibrium reactions.…”

Section: Dynamic Combinatorial Chemistry Methodsmentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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“…In the early 1990s, the number of molecules contained within 'drug discovery chemical space' was estimated to be in excess of 10 50 . [1] Attempts to search this vast chemical arena led to the advent of high-throughput screening (HTS) and combinatorial chemistry.…”

Section: High-throughput Screening and Chemical Spacementioning

confidence: 99%

“…[50] They used this 'dynamic combinatorial crystallography' (DCX) to identify inhibitors of cdk2 with DCLs composed of hydrazines and isatins to generate the corresponding hydrazones. The major advantage of this compared to standard protein DCC is firstly that identification of the binding ligand is facile, and secondly that a detailed ligand binding mode is immediately obtained.…”

Section: In An Impressive Extension Of Protein DCC Congreve Et Al Imentioning

confidence: 99%

Kinetic Template‐Guided Tethering of Fragments

2012

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This thesis is composed of two separate projects: Kinetic Template-Guided Tethering of Fragments and Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1 Degradation after DNA Damage. Kinetic Template-Guided Tethering of FragmentsThe development of a novel methodology for the site-directed discovery of small molecule, protein-binding ligands is described. The protein of interest, with a cysteine thiol (either native or engineered) adjacent to the desired binding pocket, is incubated with mixtures of low molecular weight compounds (fragments) modified with either an acrylamide or a vinyl sulfonamide capture group. Any ligand within the mixture that binds within the pocket brings the capture group into close proximity with the cysteine thiol, promoting a conjugate addition reaction at an increased rate over the background reaction. The capture reaction is designed to be slow, such that during the time course of an experiment, no adduct formation is observed unless the reaction is templated by the protein. By this method, binding ligands are rapidly identified by mass spectrometry analysis of the crude reaction mixtures. The methodology has been termed 'kinetic template-guided tethering'. Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1Degradation after DNA Damage An inhibitor described within the literature was found to attenuate the reduction of cyclin D1 after DNA damage to cells. In order to implement a two-step chemical proteomics strategy to find the molecular target of this inhibitor, a synthesis of the compound with an alkyne appendage was required. The alkyne acts as a functional handle for attachment of a reporter molecule in cells via the Huisgen cycloaddition ('Click') reaction. The design and synthesis of this inhibitor with the alkyne appendage is described.

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Detection of Ligands from a Dynamic Combinatorial Library by X‐ray Crystallography

Cited by 98 publications

References 28 publications

A Potent HIV Protease Inhibitor Identified in an Epimeric Mixture by High‐Resolution Protein Crystallography

A Potent HIV Protease Inhibitor Identified in an Epimeric Mixture by High‐Resolution Protein Crystallography

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Kinetic Template‐Guided Tethering of Fragments

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