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Title: Molecular modelling and structure-activity relationships in the cytochrome P450 enzyme superfamily
Author: Lewis, David Francis Victor
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2000
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The cytochromes P450 constitute a superfamily of over 750 individual enzymes, present in species from all five biological kingdoms, which are primarily associated with the oxidative metabolism of a vast number and variety of organic compounds, both endogenous and exogenous. These haem-thiolate enzymes bind and activate dioxygen such that mono-oxygenation of the substrate occurs, with the concomitant production of a water molecule. There is considerable current interest in the P450 mono-oxygenase system due to its major involvement in the Phase I oxidations of pharmaceuticals and, also, because of an exogenous role in the metabolic activation of carcinogens and other toxic agents. Consequently, the P450s with their particular substrate specificities represent an important area for the application of structural modelling in the rationalization of drug metabolism, and for the evaluation of potential toxicity in novel chemicals. Before crystal structures of P450s were available, it was possible to determine the molecular and electronic characteristics of P450 substrates and inducers responsible for determining enzyme specificity using a combination of molecular orbital procedures and structural modelling techniques. These investigations led to the development of COMPACT, which is a method for the prediction of P450-mediated toxicity and carcinogenicity based on the structural properties of the compound concerned. The COMPACT technique has been shown to be over 70% concordant with rodent carcinogenicity bioassay data, and this was Subsequently found to be increased by the utilization of a structural alert progra.T1l which identifies direct-acting agents. However, in order to improve the scope of the COMPACT procedure such that the methodology can be applied to human P450 substrate specificity, it was necessary to derive three-dimensional models of the enzymes themselves. Extensive modelling studies on human P450s involved in drug metabolism appear to be entirely consistent with experimental observations, thus demonstrating the reliability of this approach
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry