2213: SARS-CoV-2 helicase CACHE Challenge: Round 4

Closed since over 3 years ago

Summary

• Created: October 14, 2022
• Expires: October 21, 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.

For the fourth round we've adjusted the bad group penalty as well as starting with a different protein and ligand structure. The slightly different protein structure should subtly shift which compounds score well.

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. 18,034
• 2. Go Science 71 pts. 17,911
• 3. Anthropic Dreams 49 pts. 17,840
• 4. Marvin's bunch 33 pts. 17,751
• 5. Gargleblasters 22 pts. 17,585
• 6. Ogre's lab 14 pts. 17,276
• 7. Australia 8 pts. 16,968
• 8. L'Alliance Francophone 5 pts. 16,708
• 9. Foldit Staff 3 pts. 16,629
• 10. FamilyBarmettler 2 pts. 16,612

Top soloists

• 1. ucad 100 pts. 18,111
• 2. Sandrix72 94 pts. 17,911
• 3. guineapig 88 pts. 17,859
• 4. BootsMcGraw 82 pts. 17,841
• 5. gmn 77 pts. 17,837
• 6. Aubade01 72 pts. 17,808
• 7. fpc 67 pts. 17,751
• 8. maithra 62 pts. 17,684
• 9. spvincent 58 pts. 17,616
• 10. Galaxie 54 pts. 17,566

Comments

[rmoretti]

Objectives

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

Maximum bonus: +8 000

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.)

[Bletchley Park]

This puzzle has a bug, some protein sidechains erraticly flip back and forth while wiggling, see bug report.

[jeff101]

While running puzzle 2213 with puzzle id 2013492, I noticed there is a file called
puzzle_2013492_1.constraints What does this file do? Does 2213 have some
constraints to keep the ligand near the desired binding site and prevent the
ligand from moving outside the visible protein?

Also, is the protein in 2213 the same target protein (NSP13) as in previous CACHE
puzzles minus 8 segments? Does it have any segments that weren't in previous
CACHE puzzles (like take 2210's 199 segments and remove 10 of them while
adding 2 new ones so that 2213 ends with 191 segments)?

[jeff101]

If Foldit had one-way bands as in https://fold.it/forum/suggestions/one-directional-bands-like-bumpers-for-contact-map-puzzles a player could make his/her own constraints. For example, the player could estimate the center of the protein's binding site and put a one-way band between there and the center of the ligand. The player could then set the target length of this one-way band to the approximate radius of the protein's binding site and could make the one-way band the kind that attracts only when its present length exceeds its target length. This type of band would apply no force when the ligand is inside the protein's binding site and the usual attractive force when the ligand is outside the protein's binding site. Non-spherical binding sites could be treated using several one-way bands.