Virtual screening

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					Virtual Screening Service

Identify novel and repurposed drugs by customised virtual screening

Despite the expansion in high-throughput screening, finding new drugs is still an expensive and time-
consuming business. Virtual screening can increase drug discovery productivity by reducing the time and
expense of identifying suitable development candidates. Thousands of potential hit compounds can be
identified by virtual screening in a fraction of the time of high-throughput screening methods.

The PharmaLinks Virtual Screening Service (VSS) offers companies ready and affordable access to a
customized drug discovery service. This covers:

        o   database creation
        o   virtual screening
        o   druggability filtering
        o   and molecular docking.
Novel hit compounds can be found against selected targets, or existing compounds can be screened for
new activities (“repurposing”).

The PharmaLinks service is built on the combination of medicinal chemistry experience and advanced
computational chemistry knowledge. Our researchers have extensive experience of the drug discovery
process, including a pharmacological understanding of molecular targets, the capability to apply the
appropriate method from a wide range of computational techniques to identify new leads, and an
appreciation of synthetic issues when selecting potential hits.

Potential of the PharmaLinks Virtual Screening Service

The success of virtual screening methods to identify active new chemical entities has been well-
documented. Additionally, virtual screening methods can be used to resurrect discarded drug leads and
repurpose drugs to treat disease indications for which they were not originally intended.

The PharmaLinks Virtual Screening Service has identified lead compounds for PTP1B and FAS enzymes,
and adenosine A1 and A2 and EGF receptors. In addition, we can model targets where non-synonymous
amino acid substitutions are causing variations in drug binding, resulting in an adverse clinical response.
Our virtual screening service can then be used to identify novel hits or existing drugs that resolve this
issue of pharmacogenomic or individual genetic difference.

The PharmaLinks Virtual Screening Service provides clients with the opportunity to identify novel,
druggable hits against their target of choice, using the VSS database of over half a million compounds.
This can be expanded to include compounds from the client’s own collection, if desired.

Composition of the database

The VSS database has been generated from several commercially available databases of chemicals,
filtered for druggability by in-house algorithms. This is enhanced by commercially available databases of
drug-like molecules, the World Drug Index, and the proprietary PharmaLinks natural products and
synthetic chemical database.
The Virtual Screening Service in operation

The PharmaLinks VSS proceeds through a number of stages to deliver novel hit compounds and
repurposed drugs:

Stage 1A. Where the chosen target has three-dimensional structural information, such as X-ray
crystallography co-ordinates associated with it, we proceed directly to the screening of our database,
using a variety of docking techniques.

         Structure based focusing – Ligand pharmacophores are constructed based on the 3D structure and chemical features of
                                                          the target site.

Stage 1B. In the absence of three-dimensional structural information being available, theoretical
receptors are constructed from agonist / antagonist binding data and used to screen our database.

        Agonist / antagonist binding data-based pharmacophore searching using a series of ligands of varying activity.

Stage 2. The screening process focuses on active sites or potential allosteric sites (identified by VSS
proprietary software).
              Target sites can be probed with specific functional groups to identify key interactive regions.

Stage 3. After screening, compounds are ranked using scoring functions and further filtered using
algorithms that incorporate our researchers’ knowledge of pharmacodynamic and pharmacokinetic
parameters in drug development.

                Compounds can be filtered using pharmacodynamic and pharmacokinetic parameters.

Stage 4. Compounds can subsequently either be sourced for screening by PharmaLinks, or the data
provided to the client for their own compound assessment.
An integrated service

Integral to the Virtual Screening Service is the expertise we apply throughout the process and the
consultancy that we provide our clients. This can be extended from hit identification through the entirety of
the lead optimization process. We have a research infrastructure that includes a state-of-the-art molecular
modeling suite, equipped with over £1.0m of hardware and specialist software. Our Virtual Screening
Service researchers have extensive experience of a wide range of molecular modeling techniques,

            ab initio MO theory
            molecular mechanics and dynamics
            homology and comparative modeling
            mesoscale modeling
applied to both small molecules and biological macromolecules and have provided this service to deliver
novel hit compounds for several international pharmaceutical companies.

PharmaLinks can design specific research programmes to find new drug candidates, as specified by the
client company. We can provide additional or complementary expertise in order to boost company
research projects and can assist with defining and validating new therapeutic targets, developing assays
and screening compounds, and providing comprehensive medicinal and synthetic chemistry expertise.

PharmaLinks provides a one-stop shop for companies needing a range of expertise and facilities from
concept to compound. The whole interaction is managed by an experienced and professional team to
ensure that projects deliver results on time and within budget. Our resources are available on a contract
or collaborative basis, so that companies can engage with us in a number of ways – in tailored discovery
and development programmes, or where there is just a requirement for specific expertise or enabling
technology, such as the PharmaLinks Virtual Screening Service.

                 For further information, contact Dr Catherine Breslin, Business Development Manager,

                                                                               27 Taylor Street, Glasgow G4 0NR, UK

                                                                          Tel: 44-141-548 3904; Fax: 44-141-548-3990

    All images produced using Accelrys software, Accelrys Software Inc.