Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity
| Autor: | Richard Lonsdale, Richard A. Ward, Nicola Colclough, Eva M. Lenz, Jonathan Burgess, Nichola L. Davies, Alexandra L. Orton |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular General Chemical Engineering Library and Information Sciences 010402 general chemistry 01 natural sciences Adduct Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Molecule Reactivity (chemistry) Cysteine Molecular Targeted Therapy Acrylamides 010405 organic chemistry Chemistry General Chemistry Glutathione Combinatorial chemistry 0104 chemical sciences Computer Science Applications Warhead Covalent bond |
| Zdroj: | Journal of Chemical Information and Modeling. 57:3124-3137 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.7b00553 |
| Popis: | Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or “warhead”). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity. The half-life to adduct formation with glutathione (GSH t1/2) is a useful assay for measuring the reactivity of cysteine-targeting covalent warheads but is limited to synthesized molecules. In this manuscript we assess the ability of several experimental and computational approaches to predict GSH t1/2 for a range of cysteine target... |
| Databáze: | OpenAIRE |
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