2547: KCNT1 Round 2

Closed since about 1 year ago

Summary

• Created: December 13, 2024
• Expires: December 20, 2024 at 23:00 UTC
• Max points: 100

Description

KCNT1 is a sodium-activated potassium channel that critically influences how neurons fire. When functioning normally, KCNT1 helps maintain a healthy balance of electrical signaling in the brain. However, mutations in the KCNT1 gene can lead to a range of severe epileptic conditions such as Malignant Migrating Partial Seizures of Infancy (MMPSI).

Designing inhibitors that can precisely modulate KCNT1’s activity may offer pathways to managing or even alleviating some resulting debilitating conditions. In this puzzle series, you’ll start with a candidate molecule nestled into a KCNT1 binding pocket. Your goal is to create a potential therapeutic lead. By applying your intuition and problem-solving skills here, you could help lay the groundwork for novel treatments targeting severe pediatric epilepsies and related neurological disorders.

Top groups

• 1. Anthropic Dreams 100 pts. 23,590
• 2. VeFold 73 pts. 22,453
• 3. Contenders 52 pts. 21,759
• 4. Go Science 36 pts. 21,037
• 5. L'Alliance Francophone 24 pts. 20,621
• 6. Australia 16 pts. 20,057
• 7. Marvin's bunch 10 pts. 18,449
• 8. Team China 6 pts. 18,122
• 9. FamilyBarmettler 4 pts. 18,078
• 10. Russian team 2 pts. 17,257

Top soloists

• 71. MathePro 1 pt. 15,095
• 72. Sciren 1 pt. 14,686
• 73. biobinfbio 1 pt. 12,244
• 74. Tomoya_San123 1 pt. 0

Comments

[Sciren]

Objectives

Maximum bonus: +8000

Compound Library (max +1000)
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.)

[LociOiling]

This puzzle has the ligand at segment 141 out of 293 segments.

In most recent ligand puzzles over the past several years, the ligand is always the highest segment number.

The unusual position breaks many ligand recipes, which assume the ligand must be the last segment.

Back in the middle ages, some puzzles had ligands in the middle, and some puzzles had more than one ligand. Usually multiple ligands involved metal atoms.

[LociOiling]

I'm also noticing that recipes tend to miss gains on 2547. I didn't see this on last week's KCNT1 puzzle.

A missed gain means that the recipe failed to detect an increase in score for some reason. A "Restore Credit Best" at the end of the recipe is a partial fix, but that means the recipe wasted effort working on lower-scoring poses.

I'm also seeing a common issue involving the rotamer count. Initially, the rotamer.GetCount function returns 1 on the starting pose for 2547. After working the puzzle a little, this condition normally goes away. A simple shake and wiggle is not enough however.

The recipe Lig Detector 1.1 shows both the unusual ligand location and the rotamer count issue.

[LociOiling]

Here's an example of how to find a floating ligand. It finds the first ligand in a puzzle, which should cover small molecule design puzzles for now.

In the example, PST is a table used to the store the ligand segment and other "puzzle state" info. Some recipes might have plain global variables LIGAND and AtomsInLigand, not stored in a table.

function HasLigand () 
    local segCnt = structure.GetCount ()
    local HASLIGAND = false
    for ii = 1, structure.GetCount () do
        if structure.GetSecondaryStructure ( ii ) == "M" then
            PST.LIGAND = ii
            PST.AtomsInLigand = structure.GetAtomCount(PST.LIGAND)
            HASLIGAND = true 
            break
        end
    end
    return HASLIGAND
end