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2204: SARS-CoV-2 helicase CACHE Challenge: Round 1

Closed since over 3 years ago

Intermediate Overall Small Molecule Design

Summary

Created
September 23, 2022
Expires
Max points
100
Description

Compete in a challenge to design a drug targeting the SARS-CoV-2 helicase. Use the small molecule design tools and the compound library panel to find library compounds which bind to the active site of the enzyme.

Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.

This puzzle is part of Foldit's participation in the CACHE Challenge. From the set of all compounds submitted in the multiple rounds of puzzles, Foldit scientists will select up to 100 compounds based on the CACHE-provided criteria. Only compounds which are in a commercially available library will be selected, so it's beneficial to make use of the Compound Library panel to search for library compounds similar to your current design. But don't limit yourself to the compound library. You're more likely to get good results by alternating: optimizing the molecule with the small molecule design tools, find the closest library compound, then further refine it with the design tools.

Participation in CACHE puzzles is subject to the CACHE Terms of Participation, in particular “the Challenge IP [including Challenge Compounds] will be made freely available in the public domain pursuant to Creative Commons Attribution Only (CC-BY 4.0 or subsequent versions) licensing terms, with the intent that such Challenge IP may be Used and practiced by Users for any purpose”.

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Comments

rmoretti Staff Lv 1

Objectives

Objectives in this puzzle are driven primarily by the evaluation criteria used by CACHE.

All objectives give +1000 points when fully satisfied, for a maximum of +6 000. Most objectives have a "Show" button which should highlight areas of concern in red. Even when fully satisfied, objectives may highlight groups which may eventually contribute, so it's not recommended to keep Show on at all times.

  • Torsion Quality - Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)
  • Number of Rotatable Bonds - Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show highlights rotatable bonds.)
  • Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)
  • Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)
  • Bad Groups – Gives a bonus for avoiding groups that interfere with assays (Show highlights groups at issue.)
  • Molecular Weight – Keeps the ligand a reasonable size.

Aubade01 Lv 1

We have descended again into molecular “La La Land”.
Methylated aromatic carbons can be changed into nitrogen giving a charged species.

Aubade00/01

BootsMcGraw Lv 1

I'm not sure what we're supposed to do with this puzzle. Do we design our own compound? Or do we refine existing ones?

And how does this "library" work? I've hit the "H" key to bring it up. (H for library?? Nothing in this game makes sense, any more.) I hit the "Load Library" button… and nothing happens. Another part of the game broken, now?

rmoretti Staff Lv 1

@BootsMcGraw The Compound Library panel needs to have the small molecule selected in order to function. If you don't, the icon will be greyed out and disabled, and the "H" key won't do anything. (I agree "H" is not a great choice, but unfortunately there's only so many letters in the alphabet. – Feel free to change it in the main options panel.)

The concept is that you are able to use the small molecule tools to take the existing molecule and (re-)design it to better fit in the in the pocket. Once you get a compound that you think is reasonably decent, you can open up the Compound Library panel to search the library for available compounds which are close to your designed one. There should be a number of options, and you can play around to find one which you think still works, and then replace the current compound with the library one. You can then take that library compound and see if you can further refine it. And then you can repeat the cycle to find library compounds which are close to your refined compounds.

Keep in mind that we're only going to be experimentally testing library compounds. Any compounds that aren't in the library won't be tested as-is, but at best will be used to search for the closest on-library compound.

The concept is that this is similar to the AlphaFold panel. You design new molecules/proteins, and then ask the server if it likes this design. It either thinks the answer is close or far away, and you can look at the results to see how close you are. You can then pull down what the server thinks the answer "should be", and refine your design to either incorporate the server's changes or incorporate new changes to get the server to like the old design better. In the end, the things which are experimentally tested will be the ones where the server agrees that it likes the design.

BootsMcGraw Lv 1

@rmoretti: Yes, I had the sense to select the small molecule before attempting to open the library. The library function was not greyed out. It simply did nothing when I chose the function.

rmoretti Staff Lv 1

@BootsMcGraw We unfortunately have not been able to replicate this behavior locally. Any additional information about where and when this is occurring would be helpful. Does it always happen, or does the behavior come and go? Is there any consistency of what you are doing leading up to when things happen? If you have Foldit on multiple machines (or multiple clients) is this happening for you for all of them, or just some? What operating system (e.g. Windows, Mac, Linux) are you seeing this on? Have you heard of any other people having similar issues?