BioWorld International Correspondent
LONDON - Astex Technology Ltd. said it solved the 3-dimensional crystal structure of the human cytochrome P450 3A4 (CYP3A4), considered the most important member of the P450 family of drug metabolizing enzymes, with which as many as 50 percent of all known drugs interact.
CEO Tim Haines told BioWorld International, "This not only has revenue implications, it also demonstrates our ability to solve some of the toughest protein structures there are. [P450s] are not membrane-bound, but they are membrane-associated, and there are all sorts of difficulties, such as refolding, when they are liberated from the membrane."
This is the second P450 structure Cambridge-based Astex has solved. Haines said the company also has produced crystals of the other two P450 isoforms, though he could not comment on how long it will take to elucidate their structures.
Details of the CYP3A4 structure will be given to members of Astex's P450 consortium - AstraZeneca plc, Mitsubishi Pharma Corp. and Aventis Pharmaceuticals - for use in lead optimization. That will generate milestone payments for Astex, plus fees for co-crystallizing the protein bound to potential drug candidates.
Haines said Astex now will seek more P450 deals, but they will be different from the current agreements. "Rather than fees for service, we will now get more involved in proving the compounds."
The company said that by exploring how P450 cytochromes recognize drug molecules at the atomic level, it can rationally design drugs with better metabolic and toxicity profiles.
The P450 structures will be applied to Astex's 12 in-house programs. "This gives us a structural insight very early on to filter out compounds that interact with these enzymes and cut downstream failure," Haines said.
The company also announced a drug discovery collaboration in metabolic disorders with Mitsubishi.