2298: G-Protein-Coupled Receptor GPR133: Round 8

Closed since almost 3 years ago

Summary

• Created: May 04, 2023
• Expires: May 12, 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 8 we are using the known binding peptide, and we've increased the flexibility of protein by allowing sidechains within the pocket to be movable. You will notice that the starting score is very low. This is because the peptide does not score well for our purposes as we are looking for a drug-like small molecule. In turn this causes the objectives to return large penalties, and the compound library to return no matches. The challenge with this round will be to note some of the areas of interest shown by the peptide and transform it into a suitable small molecule.

Top groups

• 1. Anthropic Dreams 100 pts. 26,160
• 2. Ogre's lab 68 pts. 26,155
• 3. Go Science 44 pts. 25,749
• 4. Contenders 27 pts. 25,358
• 5. Gargleblasters 16 pts. 24,126
• 6. VeFold 9 pts. 23,244
• 7. FamilyBarmettler 5 pts. 22,404
• 8. AlphaFold 3 pts. 22,168
• 9. L'Alliance Francophone 1 pt. 21,939
• 10. Australia 1 pt. 21,590

Top soloists

• 1. gmn 100 pts. 26,041
• 2. Borets 94 pts. 26,028
• 3. pr0tfold 88 pts. 25,749
• 4. Bruno Kestemont 83 pts. 25,483
• 5. Bletchley Park 77 pts. 25,358
• 6. Sandrix72 72 pts. 24,967
• 7. HuubR 68 pts. 24,126
• 8. spvincent 63 pts. 23,871
• 9. guineapig 59 pts. 23,853
• 10. Galaxie 55 pts. 23,494

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.)

[WBarme1234]

Can I see the Common Compound Library somewhere in the web browsers?
I have otherwise no clues to create larger compounds by myself!

[rmoretti]

I'm not sure if there's anywhere where the full compound library can be seen online.

For most puzzles, we use the Enamine REAL set. Portions of these (though not necessarily the full 20+ billion which we are searching) can be found either on Enamine's website, or through the ZINC website.