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Vol. 29, Issue 7, 936-944, July 2001
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis,
Indiana (S.E.); Molecular Informatics, Structure & Design, Pfizer
Global Research and Development, Sandwich, Kent, United Kingdom
(M.J.d.G.); and Department of Chemistry, Washington State
University, Pullman, Washington (J.P.J.)
Structure activity relationships (SAR), three-dimensional structure
activity relationships (3D-QSAR), and pharmacophores represent useful
tools in understanding cytochrome P450 (CYP) active sites in the
absence of crystal structures for these human enzymes. These approaches
have developed over the last 30 years such that they are now being
applied in numerous industrial and academic laboratories solely for
this purpose. Such computational approaches have helped in
understanding substrate and inhibitor binding to the major human CYPs
1A2, 2B6, 2C9, 2D6, 3A4 as well as other CYPs and additionally
complement homology models for these enzymes. Similarly, these
approaches may assist in our understanding of CYP induction. This
review describes in detail the development of pharmacophores and
3D-QSAR techniques, which are now being more widely used for modeling
CYPs; the review will also describe how such approaches are likely to
further impact our active site knowledge of these omnipresent and
important enzymes.
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