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A Kaleidoscope of Colored Beads to Investigate Serine Hydrolases

Davis, MI, Simeonov, A, Lea, W and Auld, D (2014) A Kaleidoscope of Colored Beads to Investigate Serine Hydrolases. Assay and Drug Development Technologies. pp. 497-505.


The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acidÐ and nitrile-containing compounds provided structureÐactivity relationships in both potency and selectivity dimensions from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling and suggest that such profiling can be incorporated into the earliest stages of drug discovery.

Item Type: Article
Additional Information: NIBR author: Auld, D institute: NIBR contributor address: [Auld, Doug] Novartis Inst BioMed Res, Cambridge, MA USA.
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11


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