Summary of key pharmacophore features for xenobiotic-metabolizing human CYPs
| CYP | Key Features of Pharmacophore | Reference |
|---|---|---|
| 1A2 | Two 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 | |
| 2A6 | Potent CYP2A6 inhibitors do not include a lactone constituent. | Poso et al., 2001 |
| 2B6 | Substrates possess at least three hydrophobes and one hydrogen bond acceptor. | Ekins et al., 1999c |
| 2C9 | Hydrogen 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 | |
| 2D6 | Substrates 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 | |
| 2E1 | Long hydrophobic access channel | Waller et al., 1996 |
| 3A4 | Substrate 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 |