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Vol. 291, Issue 1, 424-433, October 1999
Department of Drug Disposition (S.E., S.A.W.) and Computational
Chemistry and Molecular Structure Research (G.B., J.H.W.), Lilly
Research Laboratories, Eli Lilly and Co., Lilly Corporate Center,
Indianapolis, Indiana
To gain a better understanding of the active site of cytochrome
P-450 (CYP) 3A4, a three-dimensional-quantitative structure activity
relationship model was constructed using the structures and
Km (apparent) values of 38 substrates of
human liver microsomal CYP3A4. This pharmacophore was built using the
program Catalyst and consisted of four features: two hydrogen
bond acceptors, one hydrogen bond donor, and one hydrophobic region.
The pharmacophore demonstrated a fit value (r) of
observed and expected Km (apparent) value of
0.67. The validity of the CYP3A4 substrate model was tested by twice
permuting (randomizing) the activity values and substrate structures.
The results of this validation procedure indicated that the original
model was a significant representation of the features required of
CYP3A4 substrates. The second validation method used the Catalyst model
to predict the Km (apparent) values of a
test set of structurally diverse substrates for CYP3A4 not included in
the 38 molecules used to build the model. Two fitting algorithms
included in this software were examined: fast fit and best fit. The
fast fitting method resulted in predictions for all 12 substrates that
were within 1 log unit for the residual [i.e., the difference between
predicted and observed Km (apparent)]. In
contrast, the best fit algorithm poorly predicted the
Km (apparent) values (i.e., residual >1 log
unit) of 4 of 12 substrates. These poor fits with the best fit function
suggest that the fast fit method within Catalyst is more representative
of the observed Km (apparent) values for
CYP3A4 substrates and enables good in silico prediction of this
activity. A Catalyst common features pharmacophore was also constructed
from three molecules known to activate their own metabolism included in
the 38 molecules of the initial CYP3A4 model. This demonstrated that
activators of CYP3A4 possess multiple hydrophobic regions that might
correspond with a region in the active site away from the metabolic site.
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