Frequently Asked Questions

Below you'll find answers to the most commonly asked questions about CommunityTSC (D2OL)™. If you can't find the information you're looking for here, send us an email to webmaster@childhooddiseases.org

Technical FAQ can be found in our Forum. There, many platform issues and alternate configurations are discussed at length by our robust member community.

1. What does (D2OL)™ do?
2. What is a Target?
3. What is a Candidate?
4. What is a Conformer?
5. How does Docking work?
6. Why does it take so long to dock a drug Candidate?
7. What is the Total Generations indicator on the (D2OL)™ display mean?
8. What is the Final Docked Energy of a Conformer?
9. Can I choose which Target molecules I want to work on?
10. What is a work unit?
11. How long does an average work unit take on a P3/1Ghz processor?
12. When does (D2OL)™ use my Internet Connection?
13. Do I have to be always connected to use (D2OL)™?
14. How do I know when (D2OL)™ has completed working on a Candidate?
15. What are the platform requirements for (D2OL)™?
16. Where can I find project statistics?
17. Why does my Target molecule change?
18. Does the agent checkpoint its work?
19. What are you doing with the results?

1. What does (D2OL)™ do?

Simply put, CommunityTSC Drug Design Optimization Lab (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.

2. 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.

3. 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.

4. 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.

5. 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 structure 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. When does (D2OL)™ use my Internet Connection?

(D2OL)™ only uses your internet connection when it is either retrieving candidate structures to test from The Rothberg Institute's 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.

13. Do I have to be always connected to use (D2OL)™?

No, each time (D2OL)™ connects to The Rothberg Institute's servers it will retrieve enough work to last approximately 24-36 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.

14. 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. In the future D2OL will include a progress bar and other statistics about the number of candidates and conformers that were evaluated.

15. What are the platform requirements for (D2OL)™?

See Downloading Instructions for platform requirements.

16. 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.

17. 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.

18. 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.

19. What are you doing with the results?

The Rothberg Institute is 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. Should we find candidates of interest, we are going to refine the candidates and test them in cellular and animal models of the diseases and file an Investigational New Drug Application (IND) with the US FDA.

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