2278: G-Protein-Coupled Receptor GPR133: Round 1

Closed since almost 3 years ago

Summary

• Created: March 17, 2023
• Expires: March 24, 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.

Top groups

• 1. Go Science 100 pts. 22,163
• 2. Gargleblasters 73 pts. 21,707
• 3. Anthropic Dreams 52 pts. 21,319
• 4. Contenders 36 pts. 20,984
• 5. AlphaFold 24 pts. 20,815
• 6. VeFold 16 pts. 20,643
• 7. Marvin's bunch 10 pts. 20,289
• 8. L'Alliance Francophone 6 pts. 20,216
• 9. FamilyBarmettler 4 pts. 20,006
• 10. Australia 2 pts. 19,842

Top soloists

• 11. gmn 56 pts. 21,222
• 12. NinjaGreg 52 pts. 21,216
• 13. akaaka 49 pts. 21,152
• 14. guineapig 46 pts. 20,984
• 15. BootsMcGraw 43 pts. 20,904
• 16. AlphaFold2 40 pts. 20,815
• 17. Bletchley Park 38 pts. 20,670
• 18. carxo 35 pts. 20,643
• 19. alcor29 33 pts. 20,547
• 20. Dr.Sillem 31 pts. 20,477

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. )

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, 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.)

[Sandrix72]

Torsion quality is twice here

[Sciren]

Thank you very much! It should be taken care of now.

[Sandrix72]

Please correct the error of the Small molecule properties box

[nspc]

we can't move sidechains this time ?

[Sandrix72]

I think they want to get different solutions each round. If you free them before the last round the best solutions of the first round will be sent back again and again.

[nspc]

I try different solutions each round because I "play science"

[Sandrix72]

It is correct, but if there is a "forcing effect" on the players to change previous solutions, the staff may get more/better solutions.

[jeff101]

It might not be a bad thing to try the same ligands repeatedly. In the same puzzle, a single ligand may have multiple binding sites. If a player has found one site with a good score, how does anyone know if that binding site is the best one possible? Perhaps reversing the direction of the ligand will give a better score. Perhaps moving the ligand into a different empty pocket (void) inside the protein will give a better score. Knowing more about the energy landscape for the best ligands could be helpful for science.

It is also possible that different puzzle rounds use different conformations of the same protein. Does the same ligand behave the same way in the new protein conformation? Different puzzles can also let different combinations of segments be mobile vs fixed. Different puzzles can also weight certain subscores or objective bonuses differently. How do these changes affect each of the best ligands?

[jeff101]

Nevertheless, if the Foldit scientists think players have studied certain ligands enough, it might be good to make a list of "forbidden" ligands that no longer appear as hits in searches of the compound library. These "forbidden" ligands would no longer receive the library bonus, but they could still be sent as inputs to the compound library, allowing exploration of similar but different ligands still in the compound library.