Analysis of a Large, High-Throughput Screening Data Using Recursive Partitioning

Abstract

As biological drug targets multiply through the human genome project and as the number of chemical compounds available for screening becomes very large, the expense of screening every compound against every target becomes prohibitive. We need to improve the efficiency of the drug screening process so that active compounds can be found for more biological targets and turned over to medicinal chemists for atom-by-atom optimization. We create a method for analysis of the very large, complex data sets coming from high throughput screening, and then integrate the analysis with the selection of compounds for screening so that the structure-activity rules derived from an initial compound set can be used to suggest additional compounds for screening. Cycles of screening and analysis become sequential screening rather than the mass screening of all available compounds. We extend the analysis method to deal with multivariate responses. Previously, a screening campaign might screen hundreds of thousands of compounds; sequential screening can cut the number of compounds screened by up to eighty percent. Sequential screening also gives SAR rules that can be used to mathematically screen compound collections or virtual chemical libraries.