Hit-optimization using target-directed dynamic combinatorial chemistry: Development of inhibitors of the anti-infective target 1-deoxy-D-xylulose-5-phosphate synthase

Target-directed dynamic combinatorial chemistry (tdDCC) enables the identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1‑deoxy‑d‑xylulose-5-phosphate synthase (DXS). We report the unprecedented use of tdDCC to first identify and subsequently optimize inhibitors of the anti-infective target DXS. Using tdDCC, we were able to generate acylhydrazone-based inhibitors for DXS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXS inhibitors. This approach holds the potential to expedite the drug discovery process and could be generally applied to a range of biological targets.

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Hit-Optimization Using Target-Directed Dynamic Combinatorial Chemistry: Development of Inhibitors of the Anti-Infective Target 1-Deoxy-D-Xylulose-5-Phosphate Synthase

10.26434/chemrxiv.12681761.v1 ◽

2020 ◽

Author(s):

Ravindra P. Jumde ◽

Melissa Guardigni ◽

Robin M. Gierse ◽

Alaa Alhayek ◽

Di Zhu ◽

...

Keyword(s):

Drug Discovery ◽

Combinatorial Chemistry ◽

Discovery Process ◽

Drug Discovery Process ◽

Biological Targets ◽

Dynamic Combinatorial Chemistry ◽

Structure Activity ◽

Chemistry Development ◽

Relationship Of ◽

Phosphate Synthase

Target-directed dynamic combinatorial chemistry (tdDCC) enables the identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1‑deoxy‑d‑xylulose-5-phosphate synthase (DXS). We report the unprecedented use of tdDCC to first identify and subsequently optimize inhibitors of the anti-infective target DXS. Using tdDCC, we were able to generate acylhydrazone-based inhibitors for DXS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXS inhibitors. This approach holds the potential to expedite the drug discovery process and could be generally applied to a range of biological targets.

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Formation and Trapping of the Thermodynamically Unfavoured Inverted-Hemicucurbit[6]uril

10.26434/chemrxiv.7977566 ◽

2019 ◽

Author(s):

Elena Prigorchenko ◽

Sandra Kaabel ◽

Triin Narva ◽

Anastassia Baškir ◽

Maria Fomitšenko ◽

...

Keyword(s):

Complex Formation ◽

Combinatorial Chemistry ◽

Trifluoroacetic Acid ◽

Chloride Anion ◽

Binding Affinities ◽

Dynamic Covalent Chemistry ◽

Reaction Selectivity ◽

Low Concentration ◽

Dynamic Combinatorial Chemistry ◽

First Time

Amplification of a thermodynamically unfavoured macrocyclic product through the directed shift of the equilibrium between dynamic covalent chemistry library members is difficult to achieve. We show for the first time that during condensation of formaldehyde and cis-N,N'-cyclohexa-1,2-diylurea formation of inverted-cis-cyclohexanohemicucurbit[6]uril (i-cis-cycHC[6]) can be induced at the expense of thermodynamically favoured cis-cyclohexanohemicucurbit[6]uril (cis-cycHC[6]). The formation of i-cis-cycHC[6] is enhanced in low concentration of the templating chloride anion and suppressed in excess of this template. We found that reaction selectivity is governed by the solution-based template-aided dynamic combinatorial chemistry and continuous removal of the formed cycHC[6] macrocycles from the equilibrating solution by precipitation. Notably, the i-cis-cycHC[6] was isolated with 33% yield. Different binding affinities of three diastereomeric i-cis-, cis-cycHC[6] and their chiral isomer (R,R)-cycHC[6] for trifluoroacetic acid demonstrate the influence of macrocycle geometry on complex formation.

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Faculty Opinions recommendation of RNA-selective coordination complexes identified via dynamic combinatorial chemistry.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1000946.13258 ◽

2001 ◽

Author(s):

Dennis Hall

Keyword(s):

Combinatorial Chemistry ◽

Coordination Complexes ◽

Dynamic Combinatorial Chemistry

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Adventures in molecular recognition. The ins and outs of templating

Pure and Applied Chemistry ◽

10.1351/pac200072122265 ◽

2000 ◽

Vol 72 (12) ◽

pp. 2265-2274 ◽

Cited By ~ 51

Author(s):

Jeremy K. M. Sanders

Keyword(s):

Molecular Recognition ◽

Combinatorial Chemistry ◽

Biological Systems ◽

Design Approach ◽

Supramolecular Systems ◽

Disulfide Exchange ◽

Dynamic Combinatorial Chemistry ◽

Evolutionary Features ◽

Selection Approach ◽

Porphyrin Dimers

Two different approaches are described for the creation of supramolecular systems potentially capable of recognition and catalysis. Using the design approach, we have been able to accelerate and influence two different DielsAlder reactions within the cavities of porphyrin dimers and trimers; this is templating from the outside inwards. The selection approach is a synthetic chemical attempt to capture some of the key evolutionary features of biological systems: dynamic combinatorial chemistry is used to create equilibrating mixtures of potential receptors, and then a template is used to select and amplify the desired system. Five potential reactions for such dynamic chemistry are discussed: base-catalyzed transesterification, hydrazone exchange, disulfide exchange, alkene metathesis, and Pd-catalyzed allyl exchange, and preliminary templating results (inside outwards) are presented.

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