Thursday, 2 August 2012

Twenty Years of Structural Biology in Drug Discovery

Approximately once a term, scientists working in structural biology and related areas in and near London, meet under the auspices of the London Structural Biology Club to discuss their recent research. These Club meetings generally involve four or five lectures followed by an informal discussion over beer and pizza, generously provided by a sponsoring company.

Most speakers at LSBC meetings are academic researchers and a typical presentation will highlight a novel structure or two, emphasising, for a specialist audience, some of the trickier aspects of how they were solved. The most recent meeting, however – held on 3 July 2012 in Birkbeck’s Clore Management Centre, and sponsored by specialist light scattering company Avid Nano – included one rather unusual talk. Dave Brown recently left the pharmaceutical giant Pfizer after sixteen years in its structural biology group. He now combines an academic post at the University of Kent at Canterbury with work in a new biotech company, Cangenix Molecular Solutions. During his time at Pfizer, Brown contributed his expertise in structural biology to drug discovery programmes for a wide range of cardiovascular, inflammatory and infectious diseases. The topic of his LSBC presentation was the evolution of structural biology in the pharmaceutical industry as he had experienced it during the last two decades.

The history of structural biology in drug discovery goes back a little longer than that, to the use of NMR by companies such as Abbott and Agouron to determine structure-activity relationships for compound series. The first drugs to be largely designed based on structural principles were the HIV protease inhibitors, which are covered in some depth in both section 5 and section 10 of PPS. The first protease inhibitor to be licensed for treating AIDS was Saquinavir (Invirase™), which entered the clinic in 1995, only ten years after the protease gene was first detected in the newly sequenced HIV genome.

By the mid-1990s, most major pharma companies had specialist structural biology groups. The most important developments since then have been driven by technical improvements in molecular biology, gene cloning and protein purification, and in diffraction technology. Synchrotrons such as the UK’s Diamond Light Source make their facilities available for commercial use at a price that large companies, at least, have no trouble affording. X-ray data collection is now extremely fast and can largely be automated so it has become accessible to non-expert users. Although dedicated structural biology groups in industry are no larger than they were in the 1990s, there are many more researchers there – medicinal chemists and molecular biologists – who spend some of their working life doing structural biology. Arguably, a reasonable knowledge of protein structure is essential for all scientists working in drug design.

But what, exactly, does structural biology contribute to the complex process of drug discovery? Once a likely protein target for a new discovery programme has been identified – an enzyme to be targeted by an inhibitor, for example – knowing its three-dimensional structure can help both in the selection of likely starting molecules or “hits” and in their development into “lead” compounds that are potent enough inhibitors to go forward to the later stages of drug discovery. In the related technique of fragment-based drug discovery, a huge number of very small compounds or fragments are screened against a target and those that bind to different parts of the protein’s active site are selected and linked together to form a larger and theoretically more potent compound. Typically, individual fragments bind to their target so weakly that they can only be identified experimentally rather than through computer modelling. Structural experiments can also be used to probe unexpected ligand-binding interactions, perhaps even identifying previously unknown functional binding sites, and to build selectivity for one member of a large protein family into a drug molecule. Selectivity is essential for the development of safe, non-toxic drugs that bind proteins such as kinases and G-protein coupled receptors (see section 11) that have hundreds of homologs in the human proteome.

Brown then went on to describe some of the work that he had been involved with during his career at Pfizer. Phosphodiesterases are enzymes that catalyse the breaking of phosphodiester bonds; this function is responsible for regulating the concentration of the essential cyclic nucleotide monophosphates in cells, and enzymes in this class are drug targets for a range of diseases. Cyclic GMP-specific phosphodiesterase type 5 or PDE5 is the target of Pfizer’s most famous drug, sildefanil, which is known worldwide as Viagra™ (link is to the Wikipedia entry). Researchers at Pfizer have used structure-based techniques to modify the basic structure of this compound into drugs with the potential to treat very different diseases, including Reynaud’s syndrome (in which the blood supply to the extremities is reduced in cold temperatures) and stroke recovery. The recent structure-led discovery of the mechanism by which another protein in this family, PDE4, regulates cyclic AMP may even lead to the design of drugs for a range of devastating neurological conditions including Alzheimer’s disease and schizophrenia.

Brown summed up his lecture with a series of recommendations for structural biologists working in industry (and by extension, for industrial researchers doing structural biology there). He advised them to get involved in drug discovery programmes at the earliest stage, to use structure to understand mechanisms of action rather than simply to design inhibitors and to collaborate between disciplines and sometimes even across companies. And, overall (and more prosaically), to work as quickly and cheaply as reasonable. These are not bad recommendations for academic researchers, either.

1 comment:

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