Locating Sweet Spots for Screening Hits and Evaluating Pan-Assay Interference Filters from the Performance Analysis of Two Lead-like Libraries
| Autor: | Ruth Brenk, N. Yi Mok, Sara Maxe |
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| Rok vydání: | 2013 |
| Předmět: |
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Factual General Chemical Engineering Computational biology Library and Information Sciences Ligands 01 natural sciences Article Small Molecule Libraries Assay interference 03 medical and health sciences Lead (geology) Drug Discovery High-Throughput Screening Assays Combinatorial Chemistry Techniques 030304 developmental biology Principal Component Analysis 0303 health sciences Drug discovery Chemistry General Chemistry Combinatorial chemistry Chemical space Enzymes 0104 chemical sciences Computer Science Applications Molecular Weight 010404 medicinal & biomolecular chemistry Models Chemical Algorithms Software |
| Zdroj: | Journal of Chemical Information and Modeling |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/ci300382f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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