title: Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking.
abstract: Automated docking strategies successfully applied to binding mode predictions of ligands in Cyt P450 crystal structures in an earlier study (de Graaf et al. J. Med. Chem. 2005, 7, 2308-2318) were used for the catalytic site prediction (CSP) of 65 substrates in a CYP2D6 homology model. The consideration of water molecules at predicted positions in the active site and the rescoring of pooled docking poses from four different docking programs (AutoDock, FlexX, GOLD-Goldscore, and GOLD-Chemscore) with the SCORE scoring function enabled the successful prediction of experimentally reported sites of catalysis of more than 80% of the substrates. Three docking algorithms (FlexX, GOLD-Goldscore, and GOLD-Chemscore) were subsequently used in combination with six scoring functions (Chemscore, DOCK, FlexX, GOLD, PMF, and SCORE) to assess the ability of docking-based virtual screening methods to prioritize known CYP2D6 substrates seeded into a drug-like chemical database (in the absence and presence of active-site water molecules). Finally, the optimal docking strategy in terms of virtual screening accuracy, GOLD-Chemscore with the consideration of active-site water (60% of known substrates recovered in the top 5% of the ranked drug-like database), was verified experimentally; it was successfully used to identify high-affinity CYP2D6 ligands among a larger proprietary database.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Molecular Toxicology, Division of Pharmaceutical Sciences, Department of Chemistry and Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
authors.forename: Peter H J
authors.initials: PH
authors.lastname: Keizers
authors.forename: Tushar
authors.initials: T
authors.lastname: van der Wijst
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry*; D030562:Databases, Protein; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D007527:Isoenzymes; D008024:Ligands; D014867:Water; D019389:Cytochrome P-450 CYP2D6