2591: HIKESHI Round 5

Closed since 11 months ago

Summary

• Created: March 28, 2025
• Expires: April 04, 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. 18,634
• 2. VeFold 68 pts. 18,050
• 3. Go Science 44 pts. 17,542
• 4. L'Alliance Francophone 27 pts. 17,357
• 5. FamilyBarmettler 16 pts. 16,520
• 6. Contenders 9 pts. 16,224
• 7. Australia 5 pts. 16,178
• 8. Team China 3 pts. 12,093
• 9. Marvin's bunch 1 pt. 10,303
• 10. Void Crushers 1 pt. 7,618

Top soloists

• 11. gmn 43 pts. 16,594
• 12. WBarme1234 39 pts. 16,520
• 13. BootsMcGraw 35 pts. 16,224
• 14. AlkiP0Ps 32 pts. 16,178
• 15. jamiexq 29 pts. 15,790
• 16. prkfour 26 pts. 15,494
• 17. Bletchley Park 24 pts. 15,378
• 18. zbp 21 pts. 14,302
• 19. Phobos04 19 pts. 14,263
• 20. Merf 17 pts. 13,406

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.)

[LociOiling]

The starting compound returns 79 compound library matches. "Load Library" takes a long time with this many matches (quadratic behavior).

For the starting compound, compound library match 2 seems to have the same structure as match 3c.

Many of the compounds have multiple isomers. For example, match 15 for the starting compound has isomers 15a to 15h, so eight total.

Once again, it would be nice to be able to get the SMILES string for each compound, which would make it easier to identify duplicates.

Another thought is that having a way to hide or gray out the protein would be helpful. Otherwise, the option is to drag the ligand away from the protein to get a better look. The "binding site" view option is somewhat helpful, but can still make it difficult to see the entire ligand. Options like "line" would be good in theory, but they also apply to the ligand. The combo of "ligand specific" color and "trace line" view is close to what I'm thinking of, making the ligand easy to distinguish, and thinning the bonds so it's easier to see the structure of the ligand.