2351: CACHE SARS helicase followup: Round 4

Closed since over 2 years ago

Summary

• Created: August 18, 2023
• Expires: September 15, 2023 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 similar to the starting compound 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 50 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.

For this puzzle series, we're looking to examine the Structure Activity Relationship (SAR) of the hit compounds from the previous series. As such, we ask that you attempt to find things which are similar to the starting molecule, rather than creating something completely new. There's a Similarity objective which should show when you're going too far afield.

For this round we're back to the second compound, but with a potentially different starting orientation. We've also opened up the flexibility of the sidechains in the binding pocket and loosened the thresholds of some of the objectives.

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

• 11. Australia 1 pt. 31,072
• 12. Team Schleswig-Holstein 1 pt. 30,778
• 13. Weber CHM3010 F2020 1 pt. 30,592

Top soloists

• 1. Sandrix72 100 pts. 36,100
• 2. gmn 93 pts. 35,995
• 3. LociOiling 86 pts. 34,351
• 4. ucad 79 pts. 34,221
• 5. alcor29 73 pts. 34,020
• 6. nspc 68 pts. 33,811
• 7. dcrwheeler 62 pts. 33,565
• 8. spvincent 57 pts. 33,559
• 9. Galaxie 52 pts. 33,551
• 10. Bruno Kestemont 48 pts. 33,537

Comments

[rmoretti]

Objectives

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

Maximum bonus: +10 000

Similarity (max +1000)

Gives a bonus if the current compound is "similar enough" to the starting (hit) compound. The "percent similarity" being calculated is not quite linear from a visual perspective (search for Tanimoto Similarity for further discussion), and is different from the similarity value being calculated for the Compound Library.

Compound Library (max +1000)
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.)