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Comparative reactivity analysis of small-molecule thiol surrogates.

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Petri L,Ábrányi-Balogh P,Varga PR,Imre T,Keserű GM

doi

10.1016/j.bmc.2020.115357

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

115357

issue

7

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30148-6

journal_volume

28

pub_type

杂志文章

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