Abstract Details

Poster 18: Identification of (Latent) Hit Series in Primary Screening Data

Ansgar Schuffenhauer1, Thibault Varin1, Marie-Cecile Didiot1, Christian N. Parker1
1Novartis Institues for BioMedical Research
The main goal of high-throughput screening (HTS) is to identify active chemical series rather than just individual active compounds. In light of this goal, a new method (called compound set enrichment) to identify active chemical series from primary screening data is proposed. The method employs the scaffold tree compound classification in conjunction with the Kolmogorov-Smirnov statistic to assess the overall activity of a compound set sharing a common scaffold[1]. The scaffolds are thereby defined by rule based methods, such as the scaffold tree[2] or scaffold network[3]. As there is not hard activity cut-off for individual compounds applied in compound set enrichment, this method is able to uncover “latent hits”[4] in primary screening data, which would be missed by cut-off based methods. This capability is demonstrated retrospectively on a screening set from PubChem. A prospective case study was done on a medium throughput assay for the identification of compounds modulating protein translation directed from the Internal Ribosome Entry Site (IRES) of the Encephalomyocarditis Virus (EMCV) genomic RNA. Latent hit series were identified, which could then be expanded with SAR by inventory to obtain more potent hits[5].

[1] Varin T, Gubler H, Parker CN, Zhang J-H, Raman P. Ertl P, Schuffenhauer A. Compound Set Enrichment: A Novel Approach to Analysis of Primary HTS Data. J. Chem. Inf. Model. 2010, 50:2067-2078.
[2] Schuffenhauer A, Ertl P, Roggo S, Wetzel S, Koch MA, Waldmann H. The scaffold tree—Visualization of the scaffold universe by hierarchical scaffold classification. J. Chem. Inf. Model. 2007, 47:47–58.
[3] Varin T, Schuffenhauer A, Ertl P, Renner S. Mining for Bioactive Scaffolds with Scaffold Networks: Improved Compound Set Enrichment from Primary Screening Data. J. Chem. Inf. Model 2011, 51;1528-1538.
[4] Mestres J, Veeneman GH. Identification of “Latent Hits” in Compound Screening Collections. J. Med. Chem. 2003, 46:3441-3444.
[5] Varin T, Didiot MC, parker CN, Schuffenhauer A. Latent hit series hidden in high throughput screening data. J. Med. Chem 2012, 55: 1161-1170

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