3D structure opens new avenue for drug discovery

Apr 02, 2012
3D structure opens new avenue for drug discovery
The 3D structure of SHIP2 (cyan) with the Bath-designed inhibitor molecule bound (pink and orange)

(PhysOrg.com) -- An international consortium has determined the structure of an important new drug target in complex with a synthetic molecule designed by our researchers, opening up new avenues for drug discovery.

The enzyme SHIP2, which plays a major role in cell signalling, has attracted particular attention due to its role in the negative regulation of insulin signalling and is thought to be involved in type-2 diabetes, obesity and cancer. Previous attempts to crystallise the enzyme with its natural substrate were unsuccessful, so scientists at Bath designed a new synthetic inhibitor as a mimic and with their European colleagues solved the X-ray of a key fragment of SHIP2 bound to this compound.

The research, recently published in the leading international journal ACS , was a collaborative project carried out by an international group of scientists based at the Karolinska Institutet in Stockholm Sweden, Nanyang University Singapore, the Université Libre de Bruxelles in Belgium and the University of Bath.

The scientists also undertook computational molecular dynamics on the complex, and discovered a flexible loop region of the protein that may close over the compound during binding. The researchers hope that targeting such a closed complex could provide a new strategy for the design of small-molecule drugs against SHIP2.

Professor Barry Potter, who led the enterprise together with his Wellcome Trust–funded Bath colleagues Drs Steve Mills, Andrew Riley, Gyles Cozier and Mark Thomas, said: “Such interdisciplinary collaboration represents a real route to early progress in at a time when the global pharmaceutical industry is restructuring and looking more than ever towards academic-industry partnerships for early stage drug discovery, rather than in-house R&D.

“These data further reinforce use of a new class of that we have pioneered at Bath for several years, for co-crystallisation studies.

“This work emphasises the strength of Medicinal Chemistry at the University of Bath and demonstrates that academic scientists can play a key role in drug discovery, particularly at early and innovative stages.”

The next step will be to design in silico related, but more drug-like, compounds that might bind to the closed complex of the SHIP2 enzyme. The researchers hope that others will use their work as a starting point to design such novel drug candidates.

Explore further: Pterostilbene, a molecule similar to resveratrol, as a potential treatment for obesity

More information: pubs.acs.org/doi/pdf/10.1021/cb200494d

Related Stories

Research paper on cancer drug accorded 'VIP' status

Oct 27, 2011

A paper on the anti-cancer drug Irosustat, designed by researchers at the University of Bath, has been awarded 'Very Important Paper' status by the medicinal chemistry journal ChemMedChem, including a spec ...

Novel approach to cancer drug given major boost

Jan 15, 2007

Scientists at the ProXara Biotechnology Limited have identified a way of switching off one of the key mechanisms that leads to the development and growth of a tumour. Under the Wellcome Trust's Seeding Drug Discovery initiative, ...

Spotlight on dynamic operation of enzymes

Jun 15, 2011

Our world is unique in that living organisms can undergo complex chemical reactions quickly and precisely, and sequence them together. But how can proteins integral to life effectively hasten these reactions? ...

Recommended for you

Why plants don't get sunburn

Oct 29, 2014

Plants rely on sunlight to make their food, but they also need protection from its harmful rays, just like humans do. Recently, scientists discovered a group of molecules in plants that shields them from ...

Viral switches share a shape

Oct 27, 2014

A hinge in the RNA genome of the virus that causes hepatitis C works like a switch that can be flipped to prevent it from replicating in infected cells. Scientists have discovered that this shape is shared by several other ...

'Sticky' ends start synthetic collagen growth

Oct 27, 2014

Rice University researchers have delivered a scientific one-two punch with a pair of papers that detail how synthetic collagen fibers self-assemble via their sticky ends.

Cell membranes self-assemble

Oct 27, 2014

A self-driven reaction can assemble phospholipid membranes like those that enclose cells, a team of chemists at the University of California, San Diego, reports in Angewandte Chemie.

Emergent behavior lets bubbles 'sense' environment

Oct 27, 2014

Tiny, soapy bubbles can reorganize their membranes to let material flow in and out in response to the surrounding environment, according to new work carried out in an international collaboration by biomedical ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.