An international team of scientists have opened up new avenues for drug discovery after determining the structure of an important new drug target in complex with a synthetic molecule.

            The SHIP2 enzyme (cyan) with the inhibitor bound

         (magenta and orange). You can see the flexible loop that

             researchers think closes over the binding site Credit: University of Bath

Researchers from the University of Bath designed a new synthetic inhibitor as a mimic in order to crystallise the enzyme SHIP2 – SH2-Scr homology 2-domain-containing inositol-phosphotase-2. Previous attempts to crystallise SHIP2 – which plays a role in cell signalling – with natural substrates proved unsuccessful.

Researchers in Europe solved the x-ray crystal structure of a key fragment of SHIP2 – which is through to be involved in type-2 diabetes, obesity and cancer – bound to the synthetic inhibitor.

“Such interdisciplinary collaboration represents a real route to early progress in drug discovery 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,” said Professor Barry Potter, who led the team.

Researchers 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. They hope targeting such a closed complex could provide a new strategy for the design of small molecule drugs against SHIP2.

“These data further reinforce use of a new class of synthetic molecule that we have pioneered at Bath for several years, for co-crystallisation studies,” said Potter. “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 but more drug-like compounds that might bind to the closed complex of the SHIP2 enzyme. Researchers hope that others will use their work as a starting point to design novel drug candidates.

The research – funded by the Wellcome Trust and published in ASC Chemical Biology – also included researchers from the Karolinska Institutet, Nanyan University Singapore and the Université Libre de Bruxelles.