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Library screening by fragment-based docking

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D. Huang; A. Caflisch

Journal: J. Mol. Recognit.
Year: 2010
Volume: 23
Issue: 2
Pages: 183-193
DOI: 10.1002/jmr.981
Type of Publication: Journal Article

Amyloid Precursor Protein Secretases; Cathepsin B; Cyclin-Dependent Kinase 2; Enzyme Inhibitors; Enzymes; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Structure; Peptide Fragments; Peptide Library; Protein Conformation; Protozoan Proteins; Receptor, EphB4; RNA Helicases; Serine Endopeptidases; Viral Nonstructural Proteins


We review our computational tools for high-throughput screening by fragment-based docking of large collections of small molecules. Applications to six different enzymes, four proteases, and two protein kinases, are presented. Remarkably, several low-micromolar inhibitors were discovered in each of the high-throughput docking campaigns. Probable reasons for the lack of submicromolar inhibitors are the tiny fraction of chemical space covered by the libraries of available compounds, as well as the approximations in the methods employed for scoring, and the use of a rigid conformation of the target protein.