Comparative reactivity analysis of small-molecule thiol surrogates |
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Affiliation: | 1. Research Centre for Natural Sciences, Medicinal Chemistry Research Group, H-1117 Budapest, Magyar tudósok krt 2, Hungary;2. Research Centre for Natural Sciences, MS Metabolomics Research Group, H-1117 Budapest, Magyar tudósok krt 2, Hungary |
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Abstract: | Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since covalent and non-covalent interactions are both contributing to the affinity of these compounds, evaluation of their reactivity is a key-step to find feasible warheads. There are well-established HPLC- and NMR-based kinetic assays to tackle this task, however, they use a variety of cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine and GSH. The diverse nature of the thiol sources often makes the results incomparable that prevents compiling a comprehensive knowledge base for the design of covalent inhibitors. To evaluate kinetic measurements from different sources we performed a comparative analysis of the different thiol surrogates against a designed set of electrophilic fragments equipped with a range of warheads. Our study included seven different thiol models and 13 warheads resulting in a reactivity matrix analysed thoroughly. We found that the reactivity profile might be significantly different for various thiol models. Comparing the different warheads, we concluded that – in addition to its human relevance - glutathione (GSH) provided the best estimate of reactivity with highest number of true positives identified. |
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Keywords: | Cysteine reactivity Covalent fragments Thiol surrogate Warhead Cysteamine Cysteine Glutathione Reactivity assay |
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