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X-RAY CRYSTALLOGRAPHY STRUCTURE OF HUMAN CYTOCHROME 2C9 SHOWS GOOD AGREEMENT WITH LEWIS P450 MODEL
Cytochrome P450s are a family of drug metabolising enzymes which can modify foreign molecules found in the blood and are located principally in the liver, with some enzymes found also in the lungs and at sites in the skin. These modifications can have toxic outcomes or may render a drug ineffective against the target disease. The Lewis P450 Models are being licensed for commercial use to allow drug companies, at the earliest stages of product development, to assess potential drug interactions using a panel of P450 computer models. In this way it is possible to determine which drug candidates should be ruled out of a drug development programme, or for promising candidates, what further research and development is required. This latest result represents a significant independent verification of the accuracy of Professor Lewis’ CYP2C9 model. The computer model was derived using homology modelling techniques, building a structure based on the previously published rabbit cytochrome, CYP2C5. The Lewis P450 Model took account of alterations in CYP2C9-mediated metabolism resulting from mutagenesis studies and a detailed appraisal of the known metabolism of a number of classical CYP2C9 marker substrates. The same approach was taken to generate the current range of Lewis P450 Models where encouraging similarity between predicted and actual metabolic results have been reported. Thus, the result has further significance in that it promises a similar degree of corroboration of the other computer models of human cytochrome P450s generated by Professor Lewis and provides a first in terms of matching an actual experimentally determined cytochrome structure with a modelled one. Up until now, the anticipated similarity between the Lewis P450 Models and the forthcoming X-ray structures has been inferred from the high degree of agreement between experimentally generated data and predictions of metabolism and metabolic parameters which have been made possible by the Lewis P450 Models. Since CYP2C9 is one of five liver cytochromes in humans which account collectively for the metabolism of about 90% of all drugs used in the clinic, it is anticipated that the Lewis Model will continue to find application in preclinical in silico drug assessment. “This pleasing result shows that good molecular models of use in drug testing can be developed using computer-modelling approaches. Even once all the cytochrome crystal structures are available, there will be a need to improve existing models further based on the new insights which solved structures will contribute,” said Professor David Lewis, Professor of Structural Biology, University of Surrey (UK). Dr. Mike Murray, Associate Vice President of BTG’s BioPharmaceuticals Business Unit, added, “Professor Lewis’ skill and worldwide reputation as a molecular modeller are merely confirmed by this exciting result. This should help establish further the emergent role of computer modelling as an adjunct to other approaches for early-stage compound profiling and assessment.”
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