Astex determines structure of key drug metabolising enzyme - human cytochrome P450 3A4

Astex determines structure of key drug metabolising enzyme - human cytochrome P450 3A4

CAMBRIDGE, UK, 28 October 2002 -- Astex Technology, a structure-based drug discovery company, announced that it has solved the 3-dimensional crystal structure of human cytochrome P450 3A4 (CYP3A4). This important discovery will enable drugs to be rationally designed to reduce metabolic and toxicity problems caused by their interactions with CYP3A4.

CYP3A4 is generally regarded as the most important family member of these drug metabolising enzymes. It is estimated that as many as 50 percent of all known drugs interact with this form of cytochrome P450. However, CYP3A4 is also the most poorly understood member, with respect to its drug metabolising action, and represents a major problem in drug development.

"We are delighted to announce that we have solved the crystal structure of human CYP3A4," commented Dr Harren Jhoti, Astex co-Founder and Chief Scientific Officer. "These proteins are membrane-associated, complex structures and so represent a major challenge for structure determination.

"This is the second human cytochrome P450 structure we have solved, the first being human CYP2C9, reflecting our achievements in this important area of drug discovery. By exploring how these cytochrome P450s recognise drug molecules at the atomic level, we will be able to rationally design drugs with better metabolic and toxicity profiles and thus an improved chance of making it to the market."

Cytochrome P450s are the most prominent group of drug-metabolising enzymes in humans, and consequently are of great importance to the pharmaceutical industry. Since cytochrome P450s were first linked to drug metabolism in the 1970s, many drugs have had to be withdrawn from the market or stopped in clinical trials due to adverse side effects from their interactions with these enzymes.

Four human cytochrome P450s (CYP2C9, CYP2C19, CYP2D6 and CYP3A4) account for the metabolism of nearly all clinically useful medications. The purpose of drug metabolism is to make the drugs more water-soluble so that they can be easily excreted from the body after their desired effect has been exerted.

Problems can arise when combinations of drugs are administered. Some drugs may act to increase or decrease the activity of one or more of the cytochrome P450s, which, in turn, may have an effect on how another drug is metabolised. In addition, it is known that certain individuals and populations in the world have different forms of these enzymes and hence react differently to the same drugs.

Astex Technology is a structure-based drug discovery company pioneering the use of high throughput X-ray crystallography for the rapid identification of novel drug candidates. The company's structural screening approach utilizes protein crystal structures to detect the binding of drug fragments, which are then optimized into potent lead compounds.

Source: Astex Technology  www.astex-technology.com

Posted: October 2002


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