BTG Announces High Structural Fidelity in Lewis P450 Model.
WEST CONSHOHOCKEN, Pa.--(BUSINESS WIRE)--May 10, 2004
Independently determined X-ray crystallography structure of human
cytochrome 2C9 shows very good agreement with the Lewis P450 Model
BTG (LSE: BGC), the intellectual property and technology commercialization company, today highlighted the reference in April's edition of Pharmacogenomics (5: 305-318, 2004) of the remarkable three-dimensional alignment of the structure of the human cytochrome P450, CYP2C9, depicted in Professor Lewis' 3-D Model, compared to the X-ray crystal structure solved by P.A. Williams et al. (reported in Nature 424: 464-468, 2003). The Lewis P450 Models, including those of CYP2C9, are being commercialized exclusively by BTG.
Cytochrome P450s are a family of drug metabolizing enzymes that 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 program, 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 modeling 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 modeled 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-modeling 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 modeler are merely confirmed by this exciting result. This should help further establish the emergent role of computer modelling as an adjunct to other approaches for early stage compound profiling and assessment."
BTG creates value by investing in intellectual property and technology development, and in early stage ventures. We realize value through technology licensing, patent assertion and disposal of equity investments. Through a multidisciplinary approach, we apply intellectual property and commercial expertise, together with specialist skills in science and technology, to create major product opportunities in the health and high tech sectors. BTG has commercialized important innovations, including Magnetic Resonance Imaging, Multilevel Cell (MLC) memory, and Factor IX blood clotting protein, the first recombinant treatment for Hemophilia B. BTG operates through wholly owned subsidiaries BTG international Ltd. and BTG international Inc. in the UK and USA, respectively. Further information about BTG can be found at www.btgplc.com
About Professor David FV Lewis
After graduating in Chemistry from the University of Bath, David Lewis gained an MSc in Spectroscopy from the University of Surrey and, subsequently, a PhD in Theoretical Chemistry. He was invited to join the then Biochemistry Department at Surrey as a research fellow in 1987 and was promoted to Reader in 1997, following a period of considerable advances in the structural modeling of cytochromes P450. David was made Professor in the School of Biomedical and Molecular Sciences in 2003, and he was recently awarded a DSc from the University of Bath. Professor Lewis is the author of two books on cytochromes P450, and he has over 180 publications in peer-reviewed journals. His particular research interests include structural modeling of human P450s associated with drug metabolism.
About University of Surrey
The University of Surrey is one of the UK's leading professional, scientific and technological universities with a world-class research profile and a reputation for excellence in teaching and research. The School of Biomedical and Molecular Sciences has received recognition as an international center of excellence. It received a 5** rating in the 2001 RAE as part of its submission with colleagues in the PGMS (Subjects Allied to Medicine). The School's research areas include biomaterials, analytical/chemical biology, microbial sciences, toxicology and pharmacology, nutrition and food safety, neuropharmacology, human chronobiology/ psycho-pharmacology and sleep. Further information about the University of Surrey can be found at www.surrey.ac.uk
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|Date:||May 10, 2004|
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