title: Unsupervised guided docking of covalently bound ligands.
abstract: An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand-protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.
authors.affiliation: Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire ML1 5SH, Scotland, UK. X.Fradera@organon.co.uk
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: Jasmit
authors.initials: J
authors.lastname: Kaur
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
mesh_terms: D003198:Computer Simulation; D004798:Enzymes / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012984:Software; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D004798:Enzymes; D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D013917:Thrombin