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Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking.

Journal of medicinal chemistry (2006-04-14)
Chris de Graaf, Chris Oostenbrink, Peter H J Keizers, Tushar van der Wijst, Aldo Jongejan, Nico P E Vermeulen
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Quinine, suitable for fluorescence, anhydrous, ≥98.0% (dried material, NT)
Sigma-Aldrich
Quinine, 90%