2449: Revisiting CCHFV Round 4

Closed since almost 2 years ago

Summary

• Created: April 26, 2024
• Expires: May 03, 2024 at 23:00 UTC
• Max points: 100

Description

The Crimean-Congo Hemorrhagic Fever (CCHF) is a life-threatening zoonotic disease caused by a tick-borne virus. Recent research has revealed the significant role of the viral-encoded Ovarian Tumor (OTU) deubiquitinase in the CCHFV replication process. Based on the most promising compounds, this puzzle will focus on getting an inhibitor for this protein. As the CCHFV-OTU protease interacts with another protein (ubiquitin), the interaction surface is quite large and superficial, making it a challenging binding pocket. For this round we will be focusing on the upper binding pocket. For more details check out the Crimean-Congo Hemorrhagic Fever blog post.

Top groups

• 1. Anthropic Dreams 100 pts. 25,598
• 2. Go Science 70 pts. 25,218
• 3. VeFold 47 pts. 25,052
• 4. Gargleblasters 30 pts. 24,457
• 5. Contenders 19 pts. 24,082
• 6. Australia 11 pts. 22,963
• 7. FamilyBarmettler 7 pts. 22,873
• 8. L'Alliance Francophone 4 pts. 22,867
• 9. Russian team 2 pts. 22,850
• 10. Marvin's bunch 1 pt. 22,847

Top soloists

• 1. gmn 100 pts. 25,490
• 2. nspc 92 pts. 25,188
• 3. AlphaFold2 84 pts. 25,052
• 4. Bruno Kestemont 77 pts. 24,537
• 5. HuubR 70 pts. 24,457
• 6. rosie4loop 64 pts. 24,429
• 7. jeff101 58 pts. 24,132
• 8. LociOiling 53 pts. 24,094
• 9. BootsMcGraw 48 pts. 24,082
• 10. Sandrix72 44 pts. 23,935

Comments

[rmoretti]

Objectives

Maximum bonus: +7750

Compound Library (max +750)
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.)

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

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

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.)

[HuubR]

The description above says: "For this round we will be focusing on the lower binding pocket." A bit of a surprise, because the previous round was also focusing on the lower binding pocket, and up to now they were alternating. But of course, that's not carved in stone.
The upper and lower binding pockets are shown in the Crimean-Congo Hemorrhagic Fever blog post, as reproduced below.
Left, the upper binding pocket. Right, the lower binding pocket.

In the present puzzle, the starting ligand is placed in the upper binding pocket (see the small purple dots in the picture below), but at the same time the unlocked sidechains (the darker atoms below and to the right of the small dots) are around the lower binding pocket (just like the previous round).

My guess is, it might be easier to obtain a good score by placing a ligand between the unlocked sidechains, i.e. in the lower binding pocket. That corresponds to what the description says, but it does not correspond to the position of the starting ligand.

[spvincent]

The Compound Library bonus has been reduced in recent puzzles: does this mean that you are dropping this requirement when it comes to selecting compounds for synthesis?

[jeff101]

Does Foldit's scoring for these puzzles even consider where on the protein we bind our ligands to? Is it possible to get a high score even though our ligand binds to a very different site on the protein? Are there hidden constraints in these puzzles that guide any ligand into the desired binding site?

[rosie4loop]

In the first few rounds of CCHFV (last year?) I tried to test the same ligand in the same pocket for different rounds of puzzle. But at that time the sidechain conformations of the two puzzles were different, so I got obvious clashes when I tried to model a same pose. (Screenshot https://fold.it/forum/posts/76874)

If it's the same as last year I believe currently we can move it anywhere. (Don't have time to play it this round yet, maybe can test the difference in score if I have time)

[rmoretti]

@HuubR Apologies. There was a mistake in the puzzle description. We're focusing on the pocket where the starting ligand is (the "upper" pocket).

@spvincent This project does have some chemical synthesis resources, so it's possible we select a compound which is not in the library. However, selecting on-library compounds will allow us to make more compounds more quickly with the resources we have available.

@jeff101 We're not currently imposing a pocket location objective. The pocket consideration is mostly based on where the starting molecule is.