Lessons learnt from assembling screening libraries for drug discovery for neglected diseases

Ruth Brenk, Alessandro Schipani, Daniel James, Agata Krasowski, Ian Hugh Gilbert, Julie Frearson, Paul Graham Wyatt

    Research output: Contribution to journalArticle

    154 Citations (Scopus)
    16 Downloads (Pure)

    Abstract

    To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 252 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structure-activity relationship exploration were established. Further, a literature and patent review was undertaken to extract key recognition elements of kinase inhibitors ("core fragments") to assemble a focused library for hit discovery for kinases. Computational and experimental characterisation of the general screening library revealed that the selected compounds 1) span a broad range of lead-like space, 2) show a high degree of structural integrity and purity, and 3) demonstrate appropriate solubility for the purposes of biochemical screening. The implications of this study for compound selection, especially in an academic environment with limited resources, are considered.

    Original languageEnglish
    Pages (from-to)435-444
    Number of pages10
    JournalChemMedChem
    Volume3
    Issue number3
    DOIs
    Publication statusPublished - Mar 2008

    Keywords

    • Compound selection
    • High-throughput screening (HTS)
    • Kinase inhibitors
    • Neglected diseases
    • Virtual screening
    • HTS

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