Enhanced Hit selection through Use of Molecular Descriptors in Analysis of a High-Throughput Screening Assay

• Activity Number: 472
• Type: Contributed
• Date/Time: Wednesday, August 3, 2011 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Minya Pu*+ and Karen Messer and Howard Cottam and Tomoko Hayashi and Maripat Corr and Dennis Carson
• Companies: University of California at San Diego and Moores UCSD Cancer Center and University of California at San Diego and University of California at San Diego and University of California at San Diego and University of California at San Diego
• Keywords: High-throughput screening (HTS) ; Enriched structural family ; Murcko fragments ; Daylight fingerprints ; Top X approach ; HTS hit selection

Abstract

A high-throughput screening assay of 160,000 small molecules was used to identify compounds that stimulate innate immune receptors. Hits were called using an enrichment strategy based on unsupervised chemoinformatic clustering of the compounds within the screening library, and also by a naïve 'top X' approach which ranked the compounds individually by activity level. Hits were prioritized using enrichment based on two different sets of molecular descriptors, Daylight-style functional class fingerprints and Murcko scaffolds, and the top X approach was used for the remaining data. A total of 2033 hits were carried forward to the confirmation screen, and the confirmation rate (CR) was estimated using a mixture model. The CR was 83.3% by Murcko fragments, 67.3% by Daylight clusters and 40% by Top X approach. ~10,000 compounds screened in both pilot and primary screens were also used to obtain an unbiased estimate of CR for the top X approach, as well as to compare our methods to a more computationally intensive method. Our computationally simple clustering approach performed similarly to the more computationally intensive method, and vastly outperformed the simple top X approach.