Friday, 13 February 2009

Genomes, Structural Biology and Drug Design

Professor Sir Tom Blundell, head of the School of Crystallography at Birkbeck from 1977 to 1995, returned last Monday to give an extremely well attended seminar - a tour de force of the relationship between structural biology and drug design Tom's distinguished career has also included a time as the head of the research council that funds non-medical biological research in the UK, BBSRC; he moved from Birkbeck to become head of Biological Sciences at Cambridge; and he is a director of a biotech company, Astex Therapeutics, which he founded in 1999.

Tom started his talk with a brief history of structural biology and its role in drug discovery. His personal involvement in the discipline goes back to the 1960s, when he, as a Ph.D. student, visited companies such as Eli Lilly, which manufactured insulin, with his supervisor, Dorothy Hodgkin - who solved the insulin structure, but won her Nobel prize (Chemistry, 1964) for structures of penicillin and vitamin B12.

The intervening decades have seen trends in drug discovery come and go. In the 1990s, it seemed that increases in the speed of synthesising and screening large numbers of small molecules against drug targets had made the more targeted approach of the academic structural biologists redundant. However, even the millions of compounds that can now be screened represent the tiniest fraction of "chemical space": the number of potential molecules of a size to bind to a drug target is larger than the estimated number of atoms in the universe.

And now, in the so-called age of the genome, structural biology has become an integral part of drug discovery, involved in all steps: target identification and validation, screening, and lead compound identification and optimisation. The organisation of information about sequences and structures in databases - some of which were mentioned in the PPS Bioinformatics section - began when Tom was at Birkbeck, and was spearheaded by his co-workers and collaborators, particularly Janet Thornton (now head of the EBI). The databases set up and curated by members of his Cambridge group - too many to describe properly here - are available from this page.

Some particularly useful insights arise from the relationship between the single changes in nucleic acid sequence (known as Single Nucleotide Polymorphisms, or SNPs) that are collected into databases and the structural biology of drug targets. Sometimes, with simple Mendelian diseases, one such change is sufficient to cause disease; more complex diseases arise (anything from hypertension to breast cancer to bipolar disorder) arise from interactions between many such changes that increase the chance of disease. Mapping changes in protein coding brought about by an SNP to a protein's structure can give insight into disease-causing changes in protein mechanism and lead to the identification of novel drug targets. See Burke et al. (2007), BMC Bioinformatics 8, 301 (this is an open access journal with full text available free of charge).

The drug discovery programme at Astex Therapeutics is based on experimental structural biology, on a technique known as fragment screening. In this, small chemical fragments that bind to drug targets are identified by fast X-ray crystallography. Knowing both the structures of these small compounds - which are too weak as binders to be identified by chemical means - and where they sit in a drug target's binding site enables chemists to build them out to form larger tight-binding molecules that fit into the whole site. The company's pipeline focuses on kinase inhibitors as anti-cancer drugs, and some of its lead compounds have reached early clinical trials.