TY - JOUR
T1 - Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking
AU - De Graaf, Chris
AU - Oostenbrink, Chris
AU - Keizers, Peter H.J.
AU - Van Der Wijst, Tushar
AU - Jongejan, Aldo
AU - Vermeulen, Nico P.E.
PY - 2006/4/20
Y1 - 2006/4/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33646107162&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/jm0508538
DO - https://doi.org/10.1021/jm0508538
M3 - Article
C2 - 16610785
SN - 0022-2623
VL - 49
SP - 2417
EP - 2430
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -