Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.
Article Details
- CitationCopy to clipboard
Afzelius L, Zamora I, Masimirembwa CM, Karlen A, Andersson TB, Mecucci S, Baroni M, Cruciani G
Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.
J Med Chem. 2004 Feb 12;47(4):907-14.
- PubMed ID
- 14761192 [ View in PubMed]
- Abstract
A conformer- and alignment-independent three-dimensional structure-activity relationship (3D-QSAR) model has been derived that is based on flexible molecular interaction fields calculated in GRID and the subsequent description of these fields by use of alignment-independent descriptors derived in ALMOND. The training set consisted of 22 diverse and flexible competitive inhibitors of the drug-metabolizing enzyme CYP2C9 and generated a model with r(2) of 0.81 and q(2) of 0.62. The predicitive capacity of the model was externally evaluated with a test set of 12 competitive inhibitors and 11 out of 12 were predicted within 0.5 log unit. The most relevant points of interaction in the model correlated well to the amino acids involved in CYP2C9-substrate/inhibitor binding in the active site of a CYP2C9 homology model, further validating the mechanistic sense of our model. This approach offers the possibility to derive predicitve 3D-QSAR models without the need for an alignment rule for chemically diverse ligands and in the absence of target protein crystal structure information.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Dicoumarol Cytochrome P450 2C9 Ki (nM) 1900 N/A N/A Details Fluvoxamine Cytochrome P450 2C9 Ki (nM) 8500 N/A N/A Details Miconazole Cytochrome P450 2C9 Ki (nM) 6000 N/A N/A Details Omeprazole Cytochrome P450 2C9 Ki (nM) 45000 N/A N/A Details Phenylbutazone Cytochrome P450 2C9 Ki (nM) 19000 N/A N/A Details Phenytoin Cytochrome P450 2C9 Ki (nM) 6000 N/A N/A Details Progesterone Cytochrome P450 2C9 Ki (nM) 5500 N/A N/A Details Rabeprazole Cytochrome P450 2C9 Ki (nM) 36000 N/A N/A Details Sulfaphenazole Cytochrome P450 2C9 Ki (nM) 500 N/A N/A Details Warfarin Cytochrome P450 2C9 Ki (nM) 20000 N/A N/A Details Zafirlukast Cytochrome P450 2C9 Ki (nM) 2500 N/A N/A Details