2594: HIKESHI Round 6

Closed since 11 months ago

Summary

• Created: April 03, 2025
• Expires: April 11, 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. 18,814
• 2. Go Science 65 pts. 18,246
• 3. VeFold 41 pts. 17,195
• 4. L'Alliance Francophone 24 pts. 16,895
• 5. FamilyBarmettler 14 pts. 16,763
• 6. Australia 7 pts. 16,696
• 7. Contenders 4 pts. 16,659
• 8. Void Crushers 2 pts. 12,069
• 9. Gargleblasters 1 pt. 10,405
• 10. Rechenkraft.net 1 pt. 7,417

Top soloists

• 71. tangjai 1 pt. 0
• 72. RealPerson 1 pt. 0

Comments

[Sciren]

Objectives

Maximum bonus: +10000

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.)

N-N and N-O bonds (max +1000)
Gives a bonus for avoiding molecules containing nitrogen-nitrogen (N–N) or nitrogen-oxygen (N–O) bonds (both aromatic and aliphatic). By reducing these bonds, you will be able to create more chemically realistic molecules, encouraging exploration of novel molecular designs favored by medicinal chemists.(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.)

[JellyJump]

The starting molecule is a chemically impossible/unstable gem-diol that bounces around violently when wiggled and has resulted in at least one client crash for me - is this starting molecule intended to be this or was there a mistake?!

[Sciren]

Hi @JellyJump! Unfortunately there was an error on my part in uploading this puzzle. Somewhere in the pipeline that we use to set the Small Molecule puzzles up there was an error that caused an issues with bond ordering. The intended molecule was supposed to have a carboxyl group instead of the gem-diol. I am very sorry that this missed my checks even after upload. After discussing it with the team though, we are going to go ahead and keep it as the starting compound, and use it as an opportunity to see what chemical space will ultimately be explored because of this as any molecules returned from the Compound Library search, even those in this type of state, will produce chemically phisable results. Again I am very sorry for the condition of this starting molecule and I will strive to ensure we do not have an incident like this in the future. Good luck with the rest of the puzzle run!