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  • Title: Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking.
    Author: de Graaf C, Oostenbrink C, Keizers PH, van der Wijst T, Jongejan A, Vermeulen NP.
    Journal: J Med Chem; 2006 Apr 20; 49(8):2417-30. PubMed ID: 16610785.
    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.
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