Testing small molecules for their ability to react with nucleophilic thiol-based residues such as cysteine in the early stages of discovery is a powerful method to differentiate modulators based on their mode of action. With the use of a novel fluorescence-based high throughput assay, these modulators can be identified rapidly, in parallel, for small molecule libraries using sub-milligram quantities. Thiol-containing molecules have an essential role in many biochemical and physiological reactions due to the ease of which they are oxidized and form new bonds.  Therefore, it is important to determine the reactivity of the drug candidates toward thiols in order to assess non-specific additions that can lead to side-effects in later stages of drug development.  Currently, there are no established pre-clinical high throughput assays to quickly determine the ability of small molecules towards thiol-based nucleophiles.  With the use an intrinsically fluorescent thiol-containing molecule with a large stokes shift, the electrophilic and alkylating properties of library compounds can be sensitively and selectively determined.

High throughput approach for the identification of promiscuous inhibitors among screening libraries with the use of a nucleophilic fluorescent probe

245th National Meeting (2013)

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