drug discovery

Identifying drug targets one protein at a time

Puneet Kishor, November 19th, 2013

Protein structure

The structure of human proteins defines, in part, what it is to be human. It is very expensive, as much as a couple of million USD, to determine the structure of human membrane proteins. Improvements in methods, computers and access to the complete sequence of our DNA, however, has made it possible to adopt more systematic approaches, and thus reduce the time and cost to determine the shapes of proteins. Structural genomics helps determine the 3D structures of proteins at a rapid rate and in a cost-effective manner. Structural information provides one of the most powerful means to discover how proteins work and to define ligands that modulate their function. Such ligands are starting points for drug discovery.

The Structural Genomics Consortium (SGC) at the Universities of Oxford and Toronto, solves the structures of human proteins of medical relevance and places all its findings, reagents and know-how into the public domain without restriction. Using these structures and the reagents generated as part of the structure determination process as well as the chemical probes identified, the SGC works with organizations across the world to further the understanding of the biological roles of these proteins. The SGC is particularly interested in human protein kinases, metabolism-associated proteins, integral membrane proteins, and proteins associated with epigenetics and rare diseases.

Academics work under the lamp post Drug discovery tends to be a crapshoot. As we are not good at target validation that essentially occurs in patients, more than 90% of the pioneer targets fail in Phase 2. Nevertheless, many academics and pharmas work on the same, small group of targets in competition with each other, wasting resources and careers, needlessly exposing patients to molecules destined for failure. The SGC chooses not to work under the lamp post, focusing on those targets for which there is little or no literature. This is because it is such pioneer targets, which will deliver pioneer, breakthrough medicines.

The SGC is a not-for-profit, public-private partnership, funded by public and charitable funders in Canada and UK, and eight large pharmaceutical companies – GSK, Pfizer, Novartis, Lilly, Boehringer Ingelheim, Janssen, Takeda and Abbvie, whose mandate is to promote the development of new medicines by determining 3D structures on a large scale and cost-effectively, targeting human proteins of biomedical importance and proteins from human parasites that represent potential drug targets.

SGC building leadership The SGC is now responsible for between a quarter and half of all structures deposited into the Protein Data Bank (PDB) each year. The SGC has released the structures of nearly 1500 proteins with implications to the development of new therapies for cancer, diabetes, obesity, and psychiatric disorders. As evident from the chart, SGC has published as many protein kinases as the rest of academia combined.

The SGC’s structural biology insights have allowed us to make significant progress toward the understanding of signal transduction, epigenetics and chromatin biology, and metabolic disease. The SGC has adopted the following Open Access policy—the SGC and its scientists are committed to making their research outputs (materials and knowledge) available without restriction on use. This means that the SGC promptly places its results in the public domain and agrees to not file for patent protection on any of its research outputs. This not only provides the public with this fundamental knowledge, but also allows commercial efforts and other academics to utilize the data freely and without any delay. The SGC seeks the same commitment from any research collaborator. The structural information is made available to everyone either when the structure is released by the PDB, or pre-released on www.thesgc.org.

Prof. Chas Bountra at the University of Oxford says:

“Society desperately needs new treatments for many chronic (AD, bipolar disorder, pain…) or rare diseases. This need is growing because of aging societies and diseases of modern living. As a biomedical community, we have yet to deliver truly novel treatments for many such conditions. This is not for lack of effort or resources. It is simply that these disorders are complex and there are too many variables or unknowns. It is clear that no one group or organisation can do this on their own. What we are trying to do is to bring together the best scientists from across the world, irrespective of affiliation, pooling resources and infrastructures, reducing wasteful duplicative activity to catalyse the creation of new medicines for patients. Secrecy and competition in early phases of target identification/discovery are slowing down drug discovery, making the process more difficult and more expensive.”

We at CC applaud the SGC’s commitment to open access and look to them for leadership in this arena. We believe the SGC’s findings would be a great candidate for the CC0 Public Domain Dedication because of the CC0 mark’s global recognition and a common legal status.

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