High-Throughput Mechanism of Inhibition

Author:

Davies Gareth1,Semple Hannah1,McCandless Megan1,Cairns Jonathan2ORCID,Holdgate Geoffrey A.1

Affiliation:

1. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park UK

2. Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK

Abstract

Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a modulator of enzyme activity requires an understanding of the enzyme’s mechanism and the mode of interaction of compounds. This allows an understanding of how physiological conditions in disease-relevant cells will affect inhibitor potency. As a result, there is increasing interest in evaluating hit compounds from high-throughput screens to determine their mode of interaction with the target. This work revisits the common inhibition modalities and illustrates the impact of substrate concentration relative to Km upon the pattern of changes in IC50 that are expected for increasing substrate concentration. It proposes a new, high-throughput approach for assessing mode of inhibition, incorporating analyses based on a minimal descriptive model, to deliver a workflow that allows rapid and earlier compound classification immediately after high-throughput screening.

Publisher

Elsevier BV

Subject

Molecular Medicine,Biochemistry,Analytical Chemistry,Biotechnology

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