Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases

• Published in: ChemMedChem 2008-03, Vol.3 (3), p.435-444
• Main Authors: Brenk, Ruth, Schipani, Alessandro, James, Daniel, Krasowski, Agata, Gilbert, Ian Hugh, Frearson, Julie, Wyatt, Paul Graham
• Format: Article
• Language: English
• Subjects: Chemistry, Pharmaceutical - methods; Combinatorial Chemistry Techniques - methods; compound selection; Databases, Factual; Drug Design; high-throughput screening; kinase inhibitors; neglected diseases; Peptide Library; Pharmaceutical Preparations - analysis; Pharmaceutical Preparations - chemistry; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; virtual screening
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200700139

To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 552 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1 697 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. Drug discovery on a low budget: To enable a drug discovery operation for neglected diseases, a small but diverse high‐throughput library was assembled. The selected compounds span a broad range of lead‐like space, show a high degree of structural integrity and purity, and demonstrate appropriate solubility for the purposes of biochemical screening.