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2611: HIKESHI Round 12

Closed since 10 months ago

Intermediate Overall Small Molecule Design

Summary

Created
May 15, 2025
Expires
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.

**Note: For this puzzle we are exploring a potential binding site at the C-terminal domain in the alpha-helical portion of the protein.

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Comments

Sciren Staff Lv 1

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.)