Structure Kinetics Relationships and Molecular Dynamics show crucial role for heterocycle leaving group in irreversible diacylglycerol lipase inhibitors.

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ID: 14840
2019
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Abstract
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterisation of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
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janssen2019structurejournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Janssen, Antonius P A;Hengst, Jacob van;Béquignon, Olivier;Deng, Hui;Westen, Gerard van;van der Stelt, Mario;
Journal Journal of medicinal chemistry
Year 2019
DOI
10.1021/acs.jmedchem.9b00686
URL
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