Biomedical subjects

David F V Lewis

Publications and source records attributed to David F V Lewis.

39 records · Page 3Linked to original sources

PubMed2002

Molecular modelling of the mouse cytochrome P450 CYP2F2 based on the CYP102 crystal structure template and selective CYP2F2 substrate interactions.

The results of homology modelling of the mouse cytochrome P450, CYP2F2, are reported, based on the CYP102 crystallographic template. It is found that selective CYP2F2 substrates are able to fit the putative active site of the enzyme via aromatic pi-pi stacking and, in some cases, hydrogen-bonded interactions. Two alkylnaphthalenes were investigated via the model to evaluate whether they are likely to act as CYP2F2 substrates and, of these, 2-isopropyl-naphthalene was found to fit the putative active site, whereas 2-(2-hexadecyl)naphthalene was unable to do this, due to its bulky side-chain. Consequently, it is possible to utilize homology modelling to evaluate the likelihood of enzyme-substrate selectivity for CYP2F2 and predict routes of metabolism mediated by this enzyme. This procedure can therefore be used to investigate the potential for activation of xenobiotics via this enzyme, especially those related to known CYP2F substrates, such as naphthalene.

Animals↗

PubMedDate not supplied

Molecular modeling of human cytochrome P450-substrate interactions.

The results of homology modeling of 10 human cytochrome P450 (CYP) enzymes involved in the Phase 1 metabolism of drugs and other foreign compounds are reported. The models have been constructed from the CYP102 hemoprotein domain template for which the substrate-bound crystallographic coordinates are available. Selective substrates of individual human P450s: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11 are all shown to fit within the corresponding enzymes' active sites in such a manner that is consistent with reported experimental data for both known pathways of substrate metabolism and from the results of site-directed mutagenesis, either in those particular human P450 enzymes concerned or for ones within the same subfamily. The self-consistency of these homology models indicates that they may have potential utility for the pre-screening of novel drug structures.

Cytochrome P-450 Enzyme System↗

PubMedDate not supplied

Structure-activity relationship for human cytochrome P450 substrates and inhibitors.

Criteria governing the avidity of substrate binding to human hepatic cytochromes P450 (CYP) associated with Phase 1 metabolism of drugs are described. The results of extensive quantitative structure-activity relationship (QSAR) analyses are reported for substrates of human P450s: CYPIA2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, representing the enzymes exhibiting major involvement in the metabolism of drug substrates in Homo sapiens. In particular, it is shown that hydrogen bond properties in each class of enzyme-substrate complex are especially important factors in determining substrate binding affinity towards those human P450s which are involved in drug metabolism.

Cytochrome P-450 Enzyme Inhibitors↗