Bachovchin_2014_Nat.Chem.Biol_10_656

Reference

Title : A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity - Bachovchin_2014_Nat.Chem.Biol_10_656
Author(s) : Bachovchin DA , Koblan LW , Wu W , Liu Y , Li Y , Zhao P , Woznica I , Shu Y , Lai JH , Poplawski SE , Kiritsy CP , Healey SE , DiMare M , Sanford DG , Munford RS , Bachovchin WW , Golub TR
Ref : Nat Chemical Biology , 10 :656 , 2014
Abstract : 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 acid- and nitrile-containing compounds provided structure-activity 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.
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PubMedID: 24997602
Gene_locus related to this paper: human-PPME1

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Gene_locus related to this paper: human-PPME1

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Bachovchin DA, Koblan LW, Wu W, Liu Y, Li Y, Zhao P, Woznica I, Shu Y, Lai JH, Poplawski SE, Kiritsy CP, Healey SE, DiMare M, Sanford DG, Munford RS, Bachovchin WW, Golub TR (2014)
A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity
Nat Chemical Biology 10 :656

Bachovchin DA, Koblan LW, Wu W, Liu Y, Li Y, Zhao P, Woznica I, Shu Y, Lai JH, Poplawski SE, Kiritsy CP, Healey SE, DiMare M, Sanford DG, Munford RS, Bachovchin WW, Golub TR (2014)
Nat Chemical Biology 10 :656