2585: HIKESHI Round 3

Closed since 12 months ago

Summary

• Created: March 13, 2025
• Expires: March 21, 2025 at 23:00 UTC
• Max points: 100

Description

HIKESHI Associated Leukodystrophy (HAL), also known as Hypomyelinating Leukodystrophy-13 (HLD13), is a devastating neurodegenerative disease that affects young children. Caused by specific mutations in the Hikeshi protein, HAL leads to severe neurological problems such as developmental delays, muscle stiffness (spasticity), and a smaller-than-normal head size (microcephaly). Tragically, children with HAL often experience a rapid decline or even death after a fever.

Scientists believe that these mutations make Hikeshi unstable, causing it to misfold. But there's hope! Just as small molecules have been used to help stabilize misfolded proteins in other diseases—like cystic fibrosis—we want to find molecules that could do the same for Hikeshi.

In this puzzle series, you'll start with a candidate molecule placed in a potential binding pocket on Hikeshi. Your challenge is to tweak and optimize this molecule to help stabilize the protein's structure. By using your skills, you could contribute to the discovery of a treatment for HAL and related neurodegenerative disorders.

Top groups

• 1. Anthropic Dreams 100 pts. 18,981
• 2. Go Science 56 pts. 17,743
• 3. VeFold 29 pts. 17,724
• 4. Australia 14 pts. 17,640
• 5. Contenders 6 pts. 17,245
• 6. L'Alliance Francophone 2 pts. 16,527
• 7. Void Crushers 1 pt. 14,195
• 8. FamilyBarmettler 1 pt. 10,948
• 9. Gargleblasters 1 pt. 9,647
• 10. Rechenkraft.net 1 pt. 7,414

Top soloists

• 11. dcrwheeler 42 pts. 16,825
• 12. LociOiling 38 pts. 16,686
• 13. nspc 35 pts. 16,548
• 14. christioanchauvin 31 pts. 16,527
• 15. georg137 28 pts. 16,449
• 16. NinjaGreg 26 pts. 16,038
• 17. Phobos04 23 pts. 15,208
• 18. prkfour 21 pts. 14,734
• 19. TheGUmmer 19 pts. 14,195
• 20. DScott 17 pts. 13,771

Comments

[Sciren]

Objectives

Maximum bonus: +9000

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.)

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.)

[nspc]

The starting ligand is not in the same area than previous. Is that means we should place ligand here ? It is not near the movables sidechains and the movable protein part.

Other question : is the goal is to have some interactions with the movable protein part ? How mush should we move the movable protein part ?

[meatexplosion]

They are just testing ligands in a different portion of the binding pocket of the protein. I dont believe you gain any bonus points for interacting your ligand with the movable segment. There are points to be had for properly setting the position of the movable segment however.

The Scoring for this puzzle has changed a bit. You get a 2000 point bonus for using a compound from the library rather than 1000 as before. I have also noticed the "bad groups" scoring seems more stringent than before. Functional groups I have used previously are now given negative scores.

[BootsMcGraw]

My structure had a +1000 bad groups score until I added a methyl group, and was kicked in the teeth with a -9000 bad groups score. How the ** does a carbon atom eff up a molecule 10000 points??

[BootsMcGraw]

Aaaaaaaand… I just closed two loose ends to make a ring, like I always do… and went from +1000 bad groups score to -11000 bad groups score.

We're being penalized for creativity, now?

[Floddi]

@BootsMcGraw Bad groups are depending on the chemistry. Bad groups are very reactive and therefore the molecule is unstable and your solution can't be synthezised. Normally vicinal groups will react with each other (aliphatic) so its a bad group. Rings can destabilize a structure (tension effects) so funtional groups can react more easily (i.e. condensation reactions). I.e. a chlorine on a aromatic ring system isn't that reactive while an aliphatic one is highly reactive (Sn1/2).

So yes, they're penalizing creativity if the structure becomes to unrealistic. Sometimes it makes sense to assume the products of a reaction and change the molecule accordingly. This however requieres knowledge in organic chemistry which is a pretty big topic.