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Vol. 288, Issue 1, 21-29, January 1999
Computational Chemistry and Molecular Structure Research, To begin to build an understanding of the interactions of CYP2B6 with
substrates, two different 3-dimensional quantitative structure activity
relationship (3D-QSAR) models were constructed using 16 substrates of
B-lymphoblastoid expressed CYP2B6. A pharmacophore model was built
using the program Catalyst, which was compared with a partial
least-squares (PLS) model using molecular surface-weighted holistic
invariant molecular (MS-WHIM) descriptors. The Catalyst model yielded a
3-dimensional model of the common structural features of CYP2B6
substrates, whereas PLS MS-WHIM generated a model based on statistical
analyses of molecular descriptors for size and shape of the substrate.
The pharmacophore model obtained with Catalyst consisted of three
hydrophobes and one hydrogen bond acceptor region. The cross-validated
PLS MS-WHIM model gave a good q2 value of
0.607. Size, positive electrostatic potential, hydrogen bonding
acceptor capacity, and hydrophobicity were found to be the most
relevant descriptors for the model. These models were then used to
predict the Km (apparent) values of a test set of structurally diverse substrates for CYP2B6 not included in the
model building, specifically lidocaine, amitriptyline, bupropion,
arteether, and verapamil. Overall, both 3D-QSAR methods yielded
satisfactory Km (apparent) value
predictions for the majority of the molecules in the test set. However,
PLS MS-WHIM was unable to reliably predict the
Km (apparent) value for verapamil, whereas
Catalyst did not predict the Km (apparent) value for lidocaine. In both of these cases the residual of the Km (apparent) value was greater than one
log unit. The strengths and limitations of both of these 3D-QSAR
approaches are discussed.
0022-3565/99/2881-0021$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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