2301: G-Protein-Coupled Receptor GPR133: Round 9

Closed since almost 3 years ago

Summary

• Created: May 12, 2023
• Expires: May 19, 2023 at 23:00 UTC
• Max points: 100

Description

Help us take on unexplored drug targets for brain cancer! While 1/3 of all approved drugs target G-protein-coupled receptors (GPCRs), many of these receptors remain without appropriate small molecule ligands. This is a field of growing interest with many untouched possibilities for therapeutics. The receptor GPR133 used in this puzzle (also known as ADGRD1) was identified by researchers as a critical regulator of the response to hypoxia, low levels of oxygen in bodily tissue, and tumor growth in glioblastoma, a malign and very aggressive type of brain cancer. The interest in developing therapeutics is very high, and no small-molecule (ligand) is known so far. The structure of GPR133 was determined last year and the discovery of ligands would help to create novel therapeutics. Normally a larger molecule like a peptide would be used, but we would like to design a small molecule to fit inside this binding site to understand the mechanism of the receptor.

From the set of the best compounds submitted in the upcoming puzzle rounds, if possible, we will select a few compounds for synthesis and potential in-vitro testing. Only compounds deemed synthesizable by our chemists will be selected, so it's beneficial to make use of the Compound Library panel to search for library compounds similar to your current design. However, you shouldn’t just limit yourself to the Compound Library. You're more likely to get good results by alternating: optimizing the molecule with the small molecule design tools, find the closest library compound, then further refine it with the design tools.

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

For round 9 we've picked a starting ligand, that from previous work has been found to bind well inside the pocket, and have increased the flexibility of the protein by allowing the sidechains within the pocket to be movable. The objectives have also been updated and now also include the Hydrogen Bond Donors objective. Can you find derivatives (or new compounds) in the compound library which also bind well to the protein?

Top groups

• 1. Go Science 100 pts. 28,629
• 2. Anthropic Dreams 73 pts. 28,272
• 3. Ogre's lab 52 pts. 27,141
• 4. Gargleblasters 36 pts. 26,000
• 5. Contenders 24 pts. 25,670
• 6. AlphaFold 16 pts. 25,476
• 7. VeFold 10 pts. 25,018
• 8. FamilyBarmettler 6 pts. 23,565
• 9. Australia 4 pts. 22,916
• 10. Marvin's bunch 2 pts. 22,326

Top soloists

• 31. spvincent 9 pts. 22,868
• 32. maithra 8 pts. 22,833
• 33. Dr.Sillem 7 pts. 22,620
• 34. rosie4loop 7 pts. 22,583
• 35. Flagg65a 6 pts. 22,480
• 36. Trajan464 5 pts. 22,456
• 37. fpc 5 pts. 22,326
• 38. Punzi Baker 3 4 pts. 22,202
• 39. cjddig 4 pts. 22,024
• 40. Altercomp 3 pts. 22,013

Comments

[Sciren]

Objectives

Maximum bonus: +9000

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. )

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 above 3. The upper bound of this objective is intentionally set very high to avoid directly limiting the amount of hbond donors being created. (Show highlights atoms contributing to higher cLogP.)

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.)

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.)

[LociOiling]

Segment 145 has an unlocked sidechain, and can be selected. Segment 145 doesn't turn the normal selection blue when selected. Other segments with unlocked sidechains turn blue when selected.

In a recipe, selection.IsSelected shows 145 as being selected.

Maybe something in the puzzle setup is incorrect.

The behavior for segment 145 seems a little like what happens when a ligand is selected. The sidechain and backbone inflate slightly, but the usual blue color is absent.

(Edit: hit enter too soon on the first version.)