Locating Sweet Spots for Screening Hits and EvaluatingPan-Assay Interference Filters from the Performance Analysis of TwoLead-like Libraries

摘要

The efficiency of automated compound screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their performance was investigated. Both libraries delivered screening hits across a range of targets, with the hits distributed across the entire chemical space represented by both libraries. On closer inspection, however, hit distribution was uneven across the chemical space, with enrichments observed in octants characterized by compounds at the higher end of the molecular weight and lipophilicity spectrum for lead-like compounds, while polar and sp³-carbon atom rich compounds were underrepresented among the screening hits. Based on these observations, we propose that screening libraries should not be evenly distributed in lead-like chemical space but be enriched in polar, aliphatic compounds. In conjunction with variable concentration screening, this could lead to more balancedhit rates across the chemical space and screening hits of higher ligandefficiency will be captured. Apart from chemical diversity, both screeninglibraries were shown to be clean from any pan-assay interference (PAINS)behavior. Even though some compounds were flagged to contain PAINSstructural motifs, some of these motifs were demonstrated to be lessproblematic than previously suggested. To maximize the diversity ofthe chemical space sampled in a screening campaign, we therefore considerit justifiable to retain compounds containing PAINS structural motifsthat were apparently clean in this analysis when assembling screeninglibraries.