title: Library screening by fragment-based docking.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Danzhi
authors.initials: D
authors.lastname: Huang
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D002401:Cathepsin B / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D019151:Peptide Library; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry; D020365:RNA Helicases / Q000737:chemistry; D036224:Receptor, EphB4 / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000737:chemistry; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D053829:Amyloid Precursor Protein Secretases; D002401:Cathepsin B; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors; D004798:Enzymes; D010446:Peptide Fragments; D019151:Peptide Library; D015800:Protozoan Proteins; D020365:RNA Helicases; D036224:Receptor, EphB4; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases