Table 1

Summary of key pharmacophore features for xenobiotic-metabolizing human CYPs

CYPKey Features of PharmacophoreReference
1A2Two positive potentials and two negative potentials are required for quinolone inhibitors. Fuhr et al., 1993
Planar molecules with a small volume to surface area are potent inhibitors. Lee et al., 1998
Identified positions of hydrogen bonding and hydrophobic groups for inhibitors Lozano et al., 2000
2A6Potent CYP2A6 inhibitors do not include a lactone constituent. Poso et al., 2001
2B6Substrates possess at least three hydrophobes and one hydrogen bond acceptor. Ekins et al., 1999c
2C9Hydrogen bond donor 7 Å from site of metabolism in substrates Jones et al., 1996a
The distance between the hydroxylation site and the anionic site is 7.8 Å. There is a hydrophobic zone between the hydroxylation site and the cationic site on the protein. Mancy et al., 1995 Mancy et al., 1996
Inhibitors display two cationic enzyme binding sites that were predicted to be important, along with the aromatic binding region, and a steric region. Favorable interactions occur when the substrate has a partial negative charge 10 Å from the oxidation site, with a second position of favored negative charge on the substrate 6 Å from the oxidation site and 35 degrees clockwise from the first electrostatic site. Jones et al., 1996b Rao et al., 2000
Inhibitor models had at least one hydrophobic region and one hydrogen bond acceptor. The hydrogen bond acceptor and the hydrogen bond donor/acceptor are 3.4 to 5.7 Å apart, with the hydrophobic region 3 to 5.8 Å from the hydrogen bond acceptor. Ekins et al., 2000a
2D6Substrates possess a basic nitrogen atom at either 5 or 7 Å from the site of oxidation, and aromatic rings that are coplanar. Wolff et al., 1985; Meyer et al., 1986 Islam et al., 1991
Substrates possess a carboxylate group within the protein responsible for a well defined distance of either 5 or 7 Å between basic nitrogen atom and the site of oxidation within the substrate. Koymans et al., 1992
An aspartic acid residue was coupled to the basic nitrogen atoms. de Groot et al., 1997a
Two substrate pharmacophores (one forO-dealkylation and oxidation reactions and a second one forN-dealkylation reactions catalyzed by CYP2D6) were generated. de Groot et al., 1999a,b
Inhibitor model contains a tertiary nitrogen atom (protonated at physiological pH) and a flat hydrophobic region plus two regions in which functional groups with lone pairs are allowed. Strobl et al., 1993
Inhibitor pharmacophores contain a hydrogen bond acceptor and a hydrogen bond donor and two to three hydrophobic regions. Ekins et al., 1999a
2E1Long hydrophobic access channel Waller et al., 1996
3A4Substrate model includes hydrogen bond acceptor atom 5.5 to 7.8 Å from the site of metabolism and 3 Å from the oxygen molecule associated with the heme. Lewis et al., 1996
Inhibitor pharmacophores include three hydrophobes at distances of 5.2 to 8.8 Å from a hydrogen bond acceptor, three hydrophobes at distances of 4.2 to 7.1 Å from a hydrogen bond acceptor and an additional 5.2 Å from another hydrogen bond acceptor, or one hydrophobe at distances from 8.1 to 16.3 Å from the two furthest of three hydrogen bond acceptors Ekins et al., 1999b
Substrate pharmacophore possessed two hydrogen bond acceptors, one hydrogen bond donor, and one hydrophobic region. Ekins et al., 1999d