2225: SARS-CoV-2 helicase CACHE Challenge: Round 8

Closed since over 3 years ago

Summary

• Created: November 11, 2022
• Expires: November 18, 2022 at 23:00 UTC
• 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.

This is the final round of the CACHE challenge! This round maintains the Compound Library bonus. The hydrogen bond objectives have been removed, but the influence of all hydrogen bonds have been increased.

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. 22,867
• 2. Anthropic Dreams 68 pts. 22,693
• 3. Gargleblasters 44 pts. 22,553
• 4. Go Science 27 pts. 22,472
• 5. Marvin's bunch 16 pts. 22,218
• 6. FamilyBarmettler 9 pts. 21,699
• 7. Australia 5 pts. 21,394
• 8. AlphaFold 3 pts. 20,916
• 9. L'Alliance Francophone 1 pt. 20,360
• 10. Coastal Biochemistry 1 pt. 19,219

Top soloists

• 1. ucad 100 pts. 23,230
• 2. MicElephant 94 pts. 22,867
• 3. guineapig 88 pts. 22,738
• 4. gmn 82 pts. 22,676
• 5. HuubR 76 pts. 22,524
• 6. Bruno Kestemont 71 pts. 22,472
• 7. Galaxie 66 pts. 22,365
• 8. g_b 61 pts. 22,324
• 9. LociOiling 57 pts. 22,261
• 10. fpc 53 pts. 22,218

Comments

[rmoretti]

Objectives

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

Maximum bonus: +10 000

Compound Library (max +2000)
Gives a bonus if your current compound is in the library. This uses a local cached version of the Compound Library search results to determine if the compound is in the library. If you manually create a compound that happens to be in the library (or if you load a shared solution with an on-library compound), you may need to submit the compound to the compound library search and wait to get the results back before the objective can properly recognize that the compound is in the library. (If the objective is not updating, try wiggling the structure. See this forum post for more discussion.)

Torsion Quality (max +1000)
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 (max +1000)
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 (max +1000)
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 (max +1000)
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.)

Fraction of four-bonded carbons (max +1000)
Measures how carbons with bonds to four atoms ("sp3 hybridized") there are. Too few (too many double and triple bonded carbons) is bad. (Show highlights carbon atoms at issue.)

Bad Groups (max +1000)
Gives a bonus for avoiding groups that interfere with assays, or which are far from the compounds in the library. (Show highlights groups at issue.)

Molecular Weight (max +1000)
Keeps the ligand a reasonable size.

Synthetic Accessibility (max +1000)
Keeps the ligand from going too far from the compounds in the library. (Show highlights parts of the molecule at issue.)

[jeff101]

Can we load solutions from previous CACHE puzzles into 2225? I tried some from 2222 without success.

[HuubR]

The Description above says: "The hydrogen bond objectives have been removed, but the influence of all hydrogen bonds have been increased." My understanding is, that a sort of "hydrogen bond bonus" has been added into the score. Is that correct?

Does this apply to all  hydrogen bonds made by the Ligand?
Or is there still a preference for making bonds to the donors and acceptors that were highlighted by the objectives in Puzzle 2222 (the flashing ones shown below), and not to others (like the sidechains in the foreground)?

[rmoretti]

@jeff101 For this last puzzle we're hoping to increase diversity, so the loading has been turned off.

@HuubR Correct. The influence of hydrogen bonds has been increased in the underlying (pre-objective) score. This increase should apply equally to all ligand hydrogen bonds, not just those residues of the previous round.