2264: SARS-CoV-2 Nsp3 CACHE Challenge 3: Round 1

Closed since about 3 years ago

Summary

• Created: February 10, 2023
• Expires: February 17, 2023 at 23:00 UTC
• Max points: 100

Description

Compete in a challenge to design a drug targeting the SARS-CoV-2 Nsp3 macrodomain. Use the small molecule design tools and the compound library panel to find library compounds which bind to the active site of the enzyme. -- Only compounds which come from the Compound Library panel and get the Compound Library objective bonus will be experimentally tested.

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 CACHE Challenge #3. 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 to be synthesized and experimentally tested. 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”.

Top groups

• 1. Contenders 100 pts. 27,324
• 2. Anthropic Dreams 70 pts. 26,727
• 3. Go Science 47 pts. 26,625
• 4. Gargleblasters 30 pts. 26,173
• 5. Marvin's bunch 19 pts. 25,836
• 6. Australia 11 pts. 25,740
• 7. chgf.vu.lt 7 pts. 25,030
• 8. FamilyBarmettler 4 pts. 25,009
• 9. Firesign 2 pts. 24,456
• 10. L'Alliance Francophone 1 pt. 20,579

Top soloists

• 1. grogar7 100 pts. 26,723
• 2. Bruno Kestemont 94 pts. 26,584
• 3. Sandrix72 89 pts. 26,403
• 4. guineapig 83 pts. 26,253
• 5. MicElephant 78 pts. 26,188
• 6. HuubR 73 pts. 26,173
• 7. NinjaGreg 68 pts. 26,162
• 8. spvincent 64 pts. 26,080
• 9. Galaxie 60 pts. 26,064
• 10. fpc 56 pts. 25,836

Comments

[LociOiling]

Back to the question of how the compound library works….

After removing the phosphorous as outlined above, you can continue deleting atoms to produce a smaller compound.

With the ligand selected, you can then open the Compound Library panel (hotkey "H") and use "Upload Current" to start a search. You'll need to give your new molecule a name.

The panel shows your submission is "Running".

A search normally takes a few minutes before it's "Done". The number of results is shown in the "#" column. This search found 35 results.

The "Load Library" button displays the results in a separate panel. The results are shown in order of decreasing similarity to the compound you submitted. Selecting a result and clicking "Accept Compound" replaces your new molecule with a library compound.

It's a good idea to create a segment note to identify the new compound.

Segment notes can be hidden or displayed using the hotkey "1".

It's also a good idea to take a look at the Objectives. Compound 3a was only a weak match (0.15) for the submitted molecule. It incurs a big "Bad Groups" penalty, and the cLogP is also a little high.

The three yellow atoms on the right of compound 3c are highlighted as a bad group. There's no way to directly identify which element they are. They look like sulfur, but a sulfur would normally have a hydrogen attached. The solution is to open the ligand design tool, select one of the atoms, and try substitutions. A successful substitution will have the same molecular weight and of course the same color as the mystery atom. It turns out the three mystery atoms are fluorine in this case. While some drugs do in fact contain three fluorine atoms, any fluorine is going to earn a "bad groups" deduction for this puzzle.

[Bruno Kestemont]

Unable to rotate one torsion. Shared to scientists with title "Bug, unable to rotate" (26583 pts)

[LociOiling]

I was making things too complicated, @HuubR found an easier way to remove those phosphates:

<HuubR> I may have found an easier way to get rid of a Phosphate group:
<HuubR> 1: Select the SINGLE bonded Oxygen, and delete it. It will be replaced by a Hydrogen.
<HuubR> 2: Then select the Phosphorus and change it into a Carbon. Phosphate is gone.

Step 0, starting molecule:

Step 1a: select the single-bonded oxygens:

Step 1b: delete those oxygens:

Step 2a: select the phosphorus atoms:

Step 2b: change the phosphorus to carbon:

The result is a lot easier to worith with, but it still has a cLogP of 18,446,744,073,709,551,613….

[HuubR]

Thanks, @LociOiling, for adding my method in your post (above), with pictures and all.

It looks like that very large number for cLogP is actually a small negative value. That would make sense, since this compound, with all those oxygens and nitrogens, is not hydrophobic at all.

My guess is that the value for cLogP is converted to an integer before being displayed (don't ask me why), and that it is then shown as an unsigned integer. Indeed, the value of 2⁶⁴ is 18,446,744,073,709,551,616, so the values shown here would actually be -3 (first and last pictures, above) and -2 (between steps 1 and 2).

[guineapig]