Ab Initio Molecular Modeling in the Study of Drug Metabolism
Abstract
We discuss the use of ab initio quantum mechanical methods in
drug metabolism studies. These methods require only the positions and
atomic numbers of the atoms to be specified and offer greater
transferability than conventional molecular modeling techniques. This
fact, coupled with the accuracy of our approach, permits
`computational experiments' to be performed, allowing details of
reaction mechanisms to be understood. We review the application of
these methods to the cytochrome P450 superfamily of enzymes. There is
much interest in understanding the mechanisms of these enzymes due to
their participation in a wide range of metabolic processes including
drug activation/deactivation. We find that our methods accurately
reproduce the low- to high-spin transition of the haem Fe on binding
of a substrate. Furthermore, we identify a new mechanism for the
suppression of this spin transition, namely the shortening of the bond
between the Fe atom and the coordinated S atom of the cysteine axial
ligand. These results indicate that ab initio molecular
modeling may be usefully applied in the study of drug metabolism and
that further study of intermediate states in the P450 reaction
cycle would be beneficial, particularly those which are not
accessible using conventional experimental approaches.
A full version of this paper can be downloaded in gzipped postscript. If you wish to receive a
paper copy, please email me.
Matthew Segall (mds21@phy.cam.ac.uk)
Last modified: Fri Aug 22 16:47:51 1997