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2310: KLHDC2 the Next Level: Round 1

Closed since almost 3 years ago

Intermediate Overall Small Molecule Design

Summary

Created
June 02, 2023
Expires
Max points
100
Description

Foldit players have discovered a small molecule fragment which binds well to KLHDC2. Take this starting fragment and expand upon it.

For this first round we're asking you to stick to compounds which contain compound 12 (3-furylacetic acid - the starting ligand) as a substructure, with the core molecule making the same hydrogen binding interactions that it's making in the starting structure. Take that starting structure and add groups to it to make additional interactions with the protein. Additionally, we're asking you to focus on Compound Library compounds, as that will give us the best chance of getting the molecules to test.

Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.

This is a project in collaboration with Boehringer Ingelheim. The structures of all compounds created as part of the collaboration puzzles as well as any experimental results from testing them will be made publicly available. All participants and game sponsors of current and future small molecule design games commit to complying with the Foldit Terms of Service including those pertaining to intellectual property.

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Comments

rmoretti Staff Lv 1

Objectives

Maximum bonus: +12 000

Core (max +1000)
Does the small molecule design contain the starting structure?

HBond (max +1000)
Is the ligand making hydrogen bonds to the same groups on the protein as the starting structure does? (Show highlights the groups on the protein which need to be hydrogen bonded.)

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.)

Ligand Hydrogen Bond Donors (max +1000)
Keep the number of ligand hbond donors low. (Show highlights atoms which are counted as hydrogen bond donors.)</li>

Bad Groups (max +1000)
Gives a bonus for avoiding groups that interfere with assays, or which are far from the compounds in the library. (Show highlights groups at issue.)

Element Counts (max +1000)
Gives a bonus for not having too many of particular elements. (Show highlights atoms which are over represented.)

Molecular Weight (max +1000)
Keeps the ligand a reasonable size.

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.)

Sandrix72 Lv 1

Small bug at objectives window:
Core: ligand contains 0 undesired groups (unproper text)
Element Counts: ligand contains 0 undesired groups (unproper text)

WBarme1234 Lv 1

Big problem with compound library: I don't get any large and good working ligands to choose!
How I can choose any without having a clue at all - some players did it well, but how?

Bruno Kestemont Lv 1

WBarme1234 did you try with the starting ligand ? If you (click on ligand then) load it to the library, library will return something about 35 ligand proposals after a few minutes (less than 1 hour) waiting.

None of them are good (have a core, has no objectives problems) but I thins this is not your question.

Now if you change the ligand (add a carbon, an structure) and load it again to library, you should get other results.

(personally, i tried a lot of thinks, I never got ligand proposals with the core; I've seen in the vet chat that a player succeeded).

rosie4loop Lv 1

Before they improve the compound library, external resources can be useful to get some initial ideas.
Note that the structures explored this way are not necessarily included in the compound library. I haven't been able to get the library bonus in this puzzle.

Some useful web-interface of popular public chemical database are:

There are many more public chemical database like the Enamine REAL database as mentioned in https://fold.it/puzzles/2013616#post_76418, I am not listing them here to avoid commercial promotion even though I am not connected to any of them. Many of them are the website of vendors.