2163: KLHDC2 ligand design: Round 10

Closed since over 3 years ago

Summary

• Created: June 22, 2022
• Expires: June 29, 2022 at 23:00 UTC
• Max points: 100

Description

Design a small molecule which can bind to KLHDC2! We don't want you to modify the protein, but instead use the small molecule design tools to build new small molecules which fit into the KLHDC2 binding pocket.



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



THINK SMALL. Like the previous round, we're still looking to use your designs as inspiration for similar already-purchasable molecules. We've removed the hydrophobic interaction objective to make it easier to make small compounds. But we've added a "Carboxylate Ring" objective which should give you a bonus if you make a ring within one or two atoms of the carboxylate. To give you more flexibility in this round, we've removed most of the waters and the corresponding HBond objective. We've also increased the peptide objective penalty -- we're excited to see what sort of non-peptide compounds you can come up with. See the blog post and the previous puzzles for more background information, and pay attention to the various objectives.



This is a project in collaboration with Boehringer Ingelheim & Oxford University. Boehringer Ingelheim & Oxford have committed to help evaluate and test the molecules which Foldit players have designed. 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.

Top groups

• 1. Anthropic Dreams 100 pts. 21,966
• 2. Go Science 60 pts. 21,939
• 3. Contenders 33 pts. 21,730
• 4. BIchallenge 17 pts. 21,349
• 5. Gargleblasters 8 pts. 21,316
• 6. Marvin's bunch 4 pts. 21,272
• 7. Australia 2 pts. 19,717
• 8. Team China 1 pt. 19,666
• 9. Foldit Staff 1 pt. 18,686
• 10. Beta Folders 1 pt. 17,866

Top soloists

• 1. gmn 100 pts. 21,961
• 2. pr0tfold 95 pts. 21,939
• 3. LociOiling 89 pts. 21,924
• 4. fiendish_ghoul 83 pts. 21,924
• 5. Aubade01 78 pts. 21,922
• 6. Sandrix72 74 pts. 21,916
• 7. Galaxie 69 pts. 21,790
• 8. alcor29 65 pts. 21,720
• 9. Bletchley Park 60 pts. 21,710
• 10. guineapig 56 pts. 21,648

Comments

[rmoretti]

There's a number of objectives. Most of them are there to keep the molecule going "too far" outside the range of acceptable parameters for drugs.

All objectives give +1000 points when fully satisfied, for a maximum of +12 000. Most objectives have a "Show" button which should highlight areas of concern in red. Even when fully satisfied, objectives may highlight groups which may eventually contribute, so it's not recommended to keep Show on at all times.

• Carboxylate Interaction - A bonus for keeping the hydrogen bonds the existing carboxylate is making. (Show highlights the protein atoms you need to make the hydrogen bonds to.)
• Peptide - Penalizes the formation of peptide-backbone-like groups. (Show highlights which parts of the ligand should be changed.)
• Carboxylate Ring - A bonus for making a ring near the existing carboxylate. The ring should be within one or two atoms of carboxylate.
• Torsion Quality - 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 - 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 - 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 - 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 - Keep the number of ligand hbond donors low. (Show highlights atoms contributing to higher cLogP.)
• Bad Groups - Gives a bonus for avoiding groups that aren't very drug-like, including enol, enamine, thiocarbonyl, hydroxylamines, geminal diols, alpha-beta unsaturated carbonyls, aliphatic alkanes, aliphatic alkenes, aliphatic ethers and others. (Show highlights groups at issue.)
• Element Counts - Limits certain element numbers: Desired P=0, S<=1, I<=1, Br<=1, Cl<=4, F<=4, N<=5 (Show highlights atoms of elements exceeding count.)
• Molecular Weight - Intended to keep the ligand small.
• Synthetic Accessibility - Identify molecules which are likely to be hard to make in the lab. (Show highlights regions of the molecule contributing to difficult synthesis.)