Cytochrome P450 Structural Biology
Cytochromes P450 (CYP450s) are the most significant group of drug metabolising enzymes.
In humans, the action of these proteins is the cause of adverse reactions to many marketed drugs and drug combination therapies. Many failures in drug development have also been attributed to the metabolic action of this class of proteins. For example, certain drugs may be metabolized too rapidly by CYP450s before they have a chance to be effective, while others may be broken down by CYP450s into smaller molecules which may in turn be toxic. In other cases certain drug molecules can act to inhibit the activity of a particular CYP450 isoform with the result that other drugs that are normally metabolized by the same CYP450, when given at the same time, can not be metabolized at the normal rate. This can result in the co-administered drug becoming elevated to levels which become dangerous or which can cause side effects. The insight provided by the crystal structure of CYP450s aims to improve the success rates and economics of drug development and result in safer and more effective new medicines.
Knowledge of the specific ways drugs bind to CYP450s can be exploited by Astex in novel strategies for drug design to modulate their potential for binding CYP450, while retaining compound potency and selectivity.
Astex has achieved two major scientific breakthroughs in solving the first human cytochrome P450 structures - 2C9 and 3A4 - key members of this important family of drug metabolising enzymes. Astex's proprietary P450 structural information enables the company and its collaborators to generate lead compounds with optimal DMPK properties and reduce attrition rates in drug development. Astex's scientists published the crystal structure of human P450 2C9 in 2003 in the leading science journal Nature, and of P450 3A4 in 2004 in Science.
Astex's has a number of granted patents including GB2395718 and GB 2 408 509 covering the use of the crystal structure of cytochrome P450 3A4 granted in January 2005 and October 2006 respectively ; EP 1 438 337 B1 covering crystals of cytochrome P450 2C9, structures thereof and their use which granted in Europe in September 2006 and US 7,148,046 covering crystals of human cytochrome P450 3A4 which granted on 12th December 2006.