An international consortium has determined the structure of
an important new drug target in complex with a synthetic molecule designed by University of Bath researchers, opening up new avenues
for drug discovery.
The enzyme SHIP2, which plays a major role in cell signaling,
has attracted particular attention due to its role in the negative regulation
of insulin signaling and is thought to be involved in Type 2 diabetes, obesity,
and cancer. Previous attempts to crystallize the enzyme with its natural
substrate were unsuccessful, so scientists at University of Bath
designed a new synthetic inhibitor as a mimic and with their European
colleagues solved the X-ray crystal structure of a key fragment of SHIP2 bound
to this compound.
The research, published in ACS Chemical Biology, 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 Steve Mills, Andrew Riley, Gyles
Cozier, and Mark Thomas, said: “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.
“These data further reinforce use of a new class of
synthetic molecule that we have pioneered at Bath for several years, for co-crystallization
studies.
“This work emphasizes 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.
Filed Under: Drug Discovery
