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High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Latent hit series hidden in high-throughput screening data.
Thibault Varin1, Marie-Cecile Didiot, Christian N Parker
1Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. thibault.varin@novartis.com
Journal of Medicinal Chemistry
|December 22, 2011
Summary
Compound Set Enrichment (CSE) identifies potential drug candidates ("latent hit series") missed by traditional screening methods. This novel approach analyzes activity distributions to find promising compounds, even without initial clear hits.
Area of Science:
- Drug Discovery
- Computational Chemistry
- Biochemistry
Background:
- Traditional hit identification in high-throughput screening relies on predefined thresholds.
- This can lead to the omission of potentially valuable compound series with subtle activity profiles.
- A novel method, Compound Set Enrichment (CSE), has been developed to address this limitation.
Purpose of the Study:
- To demonstrate the utility of Compound Set Enrichment (CSE) in identifying "latent hit series" that conventional methods would miss.
- To prospectively validate CSE in a cell-based screening campaign.
- To retrospectively analyze publicly available screening data using CSE.
Main Methods:
- Compound Set Enrichment (CSE) was applied to analyze the activity distribution of compound structural classes.
- A prospective cell-based assay was used to identify modulators of internal ribosome entry site (IRES)-directed translation of encephalomyocarditis virus (EMCV).
- Two assay readouts were employed: one for IRES translation and another for cell viability.
Main Results:
- Six validated latent hit series were identified using CSE in the prospective study, showing no apparent effect on cell viability.
- Further testing of new compounds within these series yielded additional hits, also without significant cytotoxicity.
- Retrospective analysis of PubChem data further supported the efficacy of CSE in identifying missed opportunities.
Conclusions:
- Compound Set Enrichment (CSE) is a powerful method for uncovering valuable hit series that are overlooked by conventional hit-calling approaches.
- CSE enhances the efficiency and scope of hit identification in high-throughput screening campaigns.
- The validated latent hit series demonstrate the potential of CSE in drug discovery pipelines.
