Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates.

Article Details

Citation

Ekins S, Bravi G, Wikel JH, Wrighton SA

Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates.

J Pharmacol Exp Ther. 1999 Oct;291(1):424-33.

PubMed ID
10490933 [ View in PubMed
]
Abstract

To gain a better understanding of the active site of cytochrome P-450 (CYP) 3A4, a three-dimensional-quantitative structure activity relationship model was constructed using the structures and K(m (apparent)) values of 38 substrates of human liver microsomal CYP3A4. This pharmacophore was built using the program Catalyst and consisted of four features: two hydrogen bond acceptors, one hydrogen bond donor, and one hydrophobic region. The pharmacophore demonstrated a fit value (r) of observed and expected K(m(apparent)) value of 0.67. The validity of the CYP3A4 substrate model was tested by twice permuting (randomizing) the activity values and substrate structures. The results of this validation procedure indicated that the original model was a significant representation of the features required of CYP3A4 substrates. The second validation method used the Catalyst model to predict the K(m(apparent)) values of a test set of structurally diverse substrates for CYP3A4 not included in the 38 molecules used to build the model. Two fitting algorithms included in this software were examined: fast fit and best fit. The fast fitting method resulted in predictions for all 12 substrates that were within 1 log unit for the residual [i.e., the difference between predicted and observed K(m(apparent))]. In contrast, the best fit algorithm poorly predicted the K(m (apparent)) values (i.e., residual >1 log unit) of 4 of 12 substrates. These poor fits with the best fit function suggest that the fast fit method within Catalyst is more representative of the observed K(m(apparent)) values for CYP3A4 substrates and enables good in silico prediction of this activity. A Catalyst common features pharmacophore was also constructed from three molecules known to activate their own metabolism included in the 38 molecules of the initial CYP3A4 model. This demonstrated that activators of CYP3A4 possess multiple hydrophobic regions that might correspond with a region in the active site away from the metabolic site.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
Cortisone acetateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
CyclosporineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
DapsoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
DexamethasoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
Dexamethasone acetateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
Dexamethasone isonicotinateCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Inducer
Details
FentanylCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
HydrocortisoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Hydrocortisone aceponateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Hydrocortisone cypionateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
Hydrocortisone phosphateCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
ParamethasoneCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
QuinidineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
RifabutinCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
SaquinavirCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
SirolimusCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
TacrolimusCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
VinblastineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
VindesineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details