Structure of new drug target determined
23 May 2012 by Evoluted New Media
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.
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.
