Astex Technology has published the first three-dimensional structure of a human cytochrome P450 protein involved in drug metabolism in Nature. The work should help researchers design drugs that are less likely to fail in development.
Cytochrome P450 proteins are responsible for metabolising foreign compounds in the body, and are involved in the breakdown of more than 90 per cent of all drugs. They cause significant attrition in the drug development process; for instance, compounds that interact with these proteins may be metabolised too rapidly or broken down into toxic metabolites, and are more prone to potentially serious drug interactions.
Astex has focused on determining the structure of one of these proteins, called CYP450 2C9, which is known to interact with the widely used anticoagulant drug warfarin. The discovery of the crystal structure has revealed a previously undescribed binding pocket in the molecule.
Harren Jhoti, Astex' founder and chief scientific officer, said: "these types of discoveries will allow our medicinal chemists to design novel drug molecules with reduced CYP450 liabilities and also generate new opportunities for Astex in the area of P450 drug activation and drug rescue."
Last year, Astex announced that it had solved the structure of another CYP450, the 3A4 isoform, but the details of this remain confidential.