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Non-stoichiometric Inhibition in High-Throughput Screening

Coan, Kristin and Ottl, Johannes and Klumpp, Martin (2011) Non-stoichiometric Inhibition in High-Throughput Screening. Expert Opinion on Drug Discovery.

Abstract

Abstract
Introduction: Over the last two decades, high-throughput screening (HTS) has become one of the key strategies for the generation of new leads. Non-stoichiometric inhibition is one of the most extensively studied mechanisms responsible for the large percentage of hit compounds from biochemical screens that cannot be developed into leads and therefore, HTS hit lists need to be sorted rapidly and efficiently into stoichiometrically binding inhibitors and compounds that affect enzyme activity non-stoichiometrically.

Areas to be covered: In this review, we first explore non-stoichiometric inhibition of enzymatic activity in biochemical screens, particularly by compound aggregation and explain the terminology we use to describe such compound behavior. We then provide a short historical overview of both academic and industrial research on compound aggregation specifically. Finally, we discuss the implications for industrial drug discovery and the measures that can be taken to identify non-stoichiometric and aggregating inhibitors early in this process.
Expert Opinion: The most pragmatic approach in a lead finding campaign is to focus on the early identification of selective and stoichiometric inhibitors. The combination of multiple approaches (assessing both activity and binding) allows the enrichment of stoichiometric inhibitors at each stage of the flowchart.

Item Type: Article
Additional Information: author can archive post-print (ie final draft post-refereeing); Restrictions: 12 month embargo for STM, Behavioural Science and Public Health Journals 18 month embargo for SSH journals
Keywords: high-throughput screening, stoichiometric binding inhibitors, non-stoichiometric inhibitors, compound aggregation
Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3945

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