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Non-Stoichiometric Inhibition in Integrated Lead Finding – A Literature Review

Klumpp, Martin (2015) Non-Stoichiometric Inhibition in Integrated Lead Finding – A Literature Review. Expert Opinion on Drug Discovery, 11 (2). pp. 149-162. ISSN 1746-04411746-045X


Introduction: Non-stoichiometric inhibition summarizes different mechanisms by which low-molecular weight compounds can reproducibly inhibit HTS and other lead finding assays without binding to a structurally defined site on their molecular target. This disqualifies such molecules from optimization by medicinal chemistry, and therefore their rapid elimination from screening hit lists is essential to productive and effective drug discovery.

Areas Covered: The review covers recent literature that either investigates the various mechanisms behind non-stoichiometric inhibition or suggests methods and readouts to identify them. Some case studies demonstrating their application are also discussed together with the underlying considerations on how to combine the various methods into project-specific flow-charts that step-by-step distill promising molecules out of raw primary hit lists. Emerging technologies to demonstrate target engagement in cells are also discussed as they should greatly facilitate the transition of lead candidates into a physiological context.

Expert Opinion: Over the last years, awareness of non-stoichiometric inhibitors within screening libraries and HTS hit lists has considerably increased among not only in the pharmaceutical industry but also among the academic drug discovery community. This has resulted in a variety of methods and approaches to detect and handle these compounds. These range from in silico approaches to flag possibly suspicious compounds over dedicated counterassays to experimentally measure specific non-stoichiometric modes of inhibition to biophysical methods that can positively demonstrate stoichiometric binding to the target. In addition, novel technologies to verify target engagement within cells are becoming available. While still a time- and resource-consuming nuisance, non-stoichiometric inhibitors therefore are not the threat to High-Throughput Screening as which they have been occasionally depicted and do not fundamentally jeopardize the discovery of low molecular weight lead and drug candiates. Rather, non-stoichiometric inhibition should be viewed as a manageable issue that with appropriate expertise can be overcome through Integrated Lead Finding.

Article Highlights:
• Awareness of non-stoichiometric inhibition has increased in the last years not only in industrial but also in academic drug discovery
• Suitable medicinal chemistry starting points can be filtered from High-Throughput Screening hit lists by counterscreens for non-stoichiometric mechanisms as well as biophysical techniques to confirm stoichiometric binding
• In silico analysis helps to prioritize compounds for experimental testing
• For each target, the most appropriate methods have to be selected and combined into a dedicated flow chart
• More and more, biochemical binding assays are complemented with methods that demonstrate cellular target engagement, which is increasingly recognized as a critical checkpoint in progressing compounds along the drug discovery pipeline

Item Type: Article
Keywords: Non-stoichiometric inhibitor
Date Deposited: 05 Dec 2015 00:45
Last Modified: 04 Jul 2016 23:45


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