New drug targets for TB through prediction/investigation of impact of resistance mutations
Honorary Director of Research and Emeritus, Department of Biochemistry, University of Cambridge
With funding from the Department of Biotechnology (DBT) in India, recently supplemented by a £2 million joint award from the UK Medical Research Council and the DBT. Professor Blundell in the team leader of Theme 2 "new drug targets for TB Treatments" of the MRC-DBT TP Project. The idea is to find innovative new ways to discover ‘next-generation’ medicines against human diseases, by coupling biological research that reveals novel drug targets with approaches in chemistry and structural biology that create potential drug candidates.
TB evolves through ‘polymorphisms’ (from the Greek multiple shapes), spontaneous changes in the letters of its DNA to create variants.
DNA sequencing data can help inform the search for new drugs, explains Professor Sir Tom Blundell.
“We can take the polymorphisms and ask questions such as ‘What does this mean for the use of current drugs?’” says Blundell. “"The nature of the polymorphisms in the TB genome sequence of an infected individual can give us information on where that person was infected and what are the drugs that might be most effective. We can then begin to look at new targets for particular polymorphisms.”
Prof Blundell plans to take the information gathered through the Chennai partnership and feed it into his drug discovery work. He takes a structural approach to solving the problem: look at the shape of the polymorphism and its protein products and try to find small molecules that can attach to and manipulate them. In essence, it’s akin to picking a lock by analysing the shape of its mechanism and trying to identify a key that could turn it, thus opening the door.
Yet even if the Chennai venture is successful, and research from the partnership leads to a revolution in how we understand and treat TB, the team recognise that this is unlikely to be enough to eradicate the disease for good.
“TB is as much a public health issue as one of infectious diseases,” says Ramakrishnan, pointing to Europe, where even before the introduction of antibiotics, the disease was already on the decline. “We need better nutrition, better air, less smoking, reductions in diabetes.”
The project activities include:
i) Undertaking sequence structure homology recognition (Fugue) and comparative modelling, and extend the M. tuberculosis structural proteome database (CHOPIN, http://mordred.bioc.cam.ac.uk/chopin/) constructed from the H37Rv strain genome. CHOPIN includes a structural analysis of known resistance mutations, and this will be enriched by the Indian dataset. Analysis will include apo, binary and ternary complexes, which will allow prediction of druggability.
(iii) Capacity build by enriching structural interactomics databases for drug discovery, including CREDO (http://marid.bioc.cam.ac.uk/credo).
(iii) Build models of mutants using Andante and assess the effects on protein stability (SDM http://mordred.bioc.cam.ac.uk/~sdm/sdm.php & mCSM http://bleoberis.bioc.cam.ac.uk/mcsm/), protein-protein interactions (mCSM-PPI) and ligands (mCSM-lig).
(iv) Create a training opportunity for a visiting Indian fellow (6 months), The MRC-DBT project supports one fellowship exchange for Indian and scholar at Cambridge.
Professor Sir Tom Blundell is quick to praise the Indian postdocs that come to work in his lab. “They tend of be naturally very inquisitive and interactive, with very enquiring minds,” he says.