Proof of Concept Pilot project:
High throughput Docking for Dengue
Scope
and objectives
Dengue
is primarily a disease of the
tropics, and the viruses that
cause it are maintained in a
cycle that involves humans and
Aedes aegypti, a domestic, day-biting
mosquito that prefers to feed
on humans. Infection with dengue
viruses produces a spectrum of
clinical illness ranging from
a non-specific viral syndrome
to severe or fatal hemorrhagic
disease. While
a major objective of pharmaceutical
research is to discover novel
medicines that improve the quality
of life of the human population,
diseases which affect mainly
the developing countries are
of limited commercial potential
under the conventional business
model of large pharma companies.
As a consequence, these diseases
are not the primary focus of
the industry, and alternative
efforts – with support
by the industry which holds the
Drug Discovery know how – are
needed to drive the discovery
of new medicines for these diseases.
In this context, we propose a
project which is aimed at the
computational screening of small
compounds – available in
public libraries – to identify
very early drug candidates, which
could interact with the molecular
targets of the dengue viruses.
Value
This
project would allow us to demonstrate
the feasibility and viability
of the Compute GRID aspect of
the Swiss Bio Grid, using an
approach which has already been
validated in industry (High Throughput
Docking on a general purpose
Compute Grid). The value of the
project can be perceived in several
dimensions:
- Establish
a computational ligand-finding
platform (server) which can
be used for many other molecular
targets, with an emphasis
on orphan diseases. The platform
would also provide centralized
access to structural data,
both for proteins and small
molecular entities.
- The
most promising compounds
identified by computational
screening will be transferred
to interested parties with
the capability to further
analyze their value in a
Drug Discovery program aimed
at treating Dengue. Such
parties may include institutions
like the Novartis Institute
for Tropical Diseases in
Singapore.
- Provide
students with the opportunity
to be confronted with Drug
Discovery problems, which
will benefit the industry
by training future highly
skilled drug discovery scientists.
- Position
Switzerland on the map of nations
searching for solutions for
orphan diseases, an activity
which is compatible with the
aspirations of its population.
This would also represent a
sensible way to support developing
countries with future government
investment.
Feasibility
The
High Throughput Docking approach
has been developed in the public
domain and a series of computational
methods and software tools are
available. These have been implemented
and validated by the pharmaceutical
industry, where considerable
know-how about their respective
value has been collected. The
transfer of this know-how, including
the running of a robust computational
system, will be a key aspect
of this pilot project. As these
lines are written, all key components
of this project are being established
at one of the member sites, demonstrating
its high probability of success.
Outlook
This
pilot project has the potential
to provide two sustained benefits:
- The
basic functionality for a
Compute Grid in Switzerland,
which can then be applied
to other computationally
intensive problems in the
life sciences.
- A
public computational ligand-finding
platform, which can be applied
to many more targets than those
of the Dengue Virus.
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