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Below you'll find answers to the most commonly asked
questions about (D2OL)™. If you can't find the
information you're looking for here, send us an email
to webmaster.
Technical FAQ can be found in our Forum.
There, many platform issues and alternate configurations
are discussed at length by our robust member community. |
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What does (D2OL)™ do?
Simply put, (D2OL)™ tests drug candidates interaction
with a Target molecule that is essential to the spread
of the disease under scrutiny. By evaluating the energy
level released by binding a small molecule drug candidate
to the surface of a larger Target molecule (D2OL)™
determines the fitness of the particular candidate
to a region of the Target structure known as the Active
Site. This process is referred to as Docking the drug
candidate to the target.
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What is a Target?
A Target molecule is a large protein or enzyme that
has been found to play a critical role in the advancement
of a disease in an organism. Sometimes the Target
is a lethal component that destroys infected cells,
much like a venom or a poison. Other times it is a
molecule that plays a vital part in supporting the
disease's spread. By neutralizing the Target, pharmaceuticals
eliminate the effects or the propagation of the disease
in an organism.
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What is a Candidate?
A candidate is a small, readily available molecule
that might have an impact on the Target structure's
behavior in an organism when the two are combined.
When a candidate binds well to the Target it is said
to have high affinity. This normally indicates an
effect on the Target's behavior, but this can only
be verified in vitro in a lab. Virtual drug screening
allows us to narrow the potential candidates to be
tested in a lab by many orders of magnitude, saving
time and money necessary to develop effective drugs
for diseases.
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What is a Conformer?
A conformer is a 3 dimensional configuration of a
particular candidate structure. Drug molecules have
torsional bonds that can be oriented in different
ways, which creates millions of derivative structures
that have the same atomic composition but different
spatial configurations. These structures are called
Conformers.
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How does Docking work?
Docking a drug candidate to a Target is essentially
like testing the fitness of a key to a lock. The Active
Site on the Target is the lock, and the drug candidate
is the key. When the two structures are placed next
to each other the bonding energy of the docked structures
is simulated. Lower scores represent "better"
candidates that can be used for further investigation
into the real life effects of the drug candidate on
the disease.
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Why does it take so long to dock a drug Candidate?
Each docking is actually very rapid, but we need
to test different configurations of the candidate
on the active site of the larger Target molecule.
By orienting and twisting the bonds of the small molecule
we actually create millions of 3 dimensional configurations
of the candidate (Conformers) that need to be docked
before we can determine what structure produces the
lowest docking energy. As a result, the entire exhaustive
process can take a few hours per candidate.
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What is the Total Generations indicator on the (D2OL)™
display mean?
(D2OL)™ uses a Genetic Algorithm to optimize
the docking process. As such, mutations in the orientation
of the torsion bonds of the candidate are performed
to create different generations of the candidate to
identify the lowest docked energy state.
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What is the Final Docked Energy of a Conformer?
The Final Docked Energy figure represents the energy
released by the combined candidate structure and the
Target. Lower scores generally indicate a better fit.
This includes negative values.
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Can I choose which Target molecules I want to work
on?
No, these are organized to most efficiently complete
the docking tasks that are created. The system does
not currently allow for selection of Targets.
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What is a work unit?
A work unit is a series of energy evaluations of
a small molecule drug candidate docked to a macromolecule
(Target). Depending on the Target under scrutiny (D2OL)™
will perform between 15 and 30 runs each containing
over 500,000 individual energy evaluations of the
drug candidate.
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How long does an average work unit take on a P3/1Ghz
processor?
A work unit (docking task) for will take approximately
2 hours on a P3/1Ghz machine if you have the GUI closed.
If you have the GUI open and displaying the rendered
molecule it will take approximately 3 hours.
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When does (D2OL)™ use my Internet Connection?
(D2OL)™ only uses your internet connection when
it is either retrieving candidate structures to test
from our servers, or when it is reporting results
after the successful completion of a work unit. Because
the candidate structures are very small - on the order
of 1kb-2kb, the bandwidth requirements are minimal.
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Do I have to be always connected to use (D2OL)™?
No, each time (D2OL)™ connects to our servers
it will retrieve enough work to last approximately
12-24 hours. In addition, results are queued until
your computer establishes an internet connection and
are then reported to the server, so no results are
lost if you shut down your computer or disconnect
from the internet.
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How do I know when (D2OL)™ has completed working
on a Candidate?
When (D2OL)™ completes its work on a candidate
the list of Top conformers will be cleared and a new
candidate will be displayed.
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Where can I find project statistics?
You can find the best structures found for each target,
total candidates evaluated, and individual node contributions
to the project using the main menu statistics button
or just click
here. In addition we are evaluating the creation
of Teams amongst community members.
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Why does my Target molecule change?
The agent will switch between targets depending on
what the tasks that it downloads require. Each time
the agent retrieves tasks, it will swap the target
rendering to reflect any changes in target focus.
For example, your agent might work on a docking for
a Smallpox target, and then switch to Anthrax Lethal
Factor automatically.
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Does the agent checkpoint its work?
No, if you stop a run before you have completed all
the conformers for a candidate, the docking will be
aborted. The genetic algorithm that creates the conformers
is such that each new conformer depends on the prior
one and a random seed. We are currently working on
implementing intra-docking checkpoints.
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What are you doing with the results?
We are the recipient of the results and we perform
the initial post processing analysis internally with
the collaboration of our advisors and scientists,
who are experts in statistical mechanics and structure
based drug design. We will develop any promising leads
with the help of our collaborators.
this page last
reviewed October 1, 2004
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