J Chem Inf Model - Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries.

Tópicos

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Resumo

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 sp(3)-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 balanced hit rates across the chemical space and screening hits of higher ligand efficiency will be captured. Apart from chemical diversity, both screening libraries were shown to be clean from any pan-assay interference (PAINS) behavior. Even though some compounds were flagged to contain PAINS structural motifs, some of these motifs were demonstrated to be less problematic than previously suggested. To maximize the diversity of the chemical space sampled in a screening campaign, we therefore consider it justifiable to retain compounds containing PAINS structural motifs that were apparently clean in this analysis when assembling screening libraries.

Resumo Limpo

effici autom compound screen heavili influenc design qualiti screen librari use recent report assembl one divers one targetfocus leadlik screen librari use data enzymebas screen conduct use librari perform investig librari deliv screen hit across rang target hit distribut across entir chemic space repres librari closer inspect howev hit distribut uneven across chemic space enrich observ octant character compound higher end molecular weight lipophil spectrum leadlik compound polar spcarbon atom rich compound underrepres among screen hit base observ propos screen librari even distribut leadlik chemic space enrich polar aliphat compound conjunct variabl concentr screen lead balanc hit rate across chemic space screen hit higher ligand effici will captur apart chemic divers screen librari shown clean panassay interfer pain behavior even though compound flag contain pain structur motif motif demonstr less problemat previous suggest maxim divers chemic space sampl screen campaign therefor consid justifi retain compound contain pain structur motif appar clean analysi assembl screen librari

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