2082: VHL ligand design: Round 7

Closed since about 4 years ago

Summary

• Created: December 15, 2021
• Expires: December 22, 2021 at 23:00 UTC
• Max points: 100

Description

Design a small molecule which can bind VHL! This is the seventh in a series of puzzles using the small molecule design tools to design small molecule binders to the von Hippel-Lindau E3 ubiquitin ligase. We don't want you to modify the protein, but instead we'd like you to build new small molecules which fit into the VHL pocket. See the new "Inside the Pocket" and "Fun with Fragments!" tutorials to learn how to use the small molecule 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



As with all the puzzles in this series, we're hoping you can continue to redesign the ligand to decrease the polarity and to change the center five member ring. Starting from the same place as Round 6, for Round 7 we've tightened the TPSA objective even further (and relaxed the cLogP objective). Can you find designs that preserve the existing interactions with the protein, while removing the "extra" polar groups?



This is a project in collaboration with Boehringer Ingelheim. Boehringer Ingelheim has committed to help evaluate and test the molecules which Foldit players have designed. All compounds created as part of the collaboration puzzles will be made publicly available. Experimental results from testing the molecules will also be released publicly. 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. Contenders 100 pts. 26,256
• 2. Anthropic Dreams 71 pts. 26,110
• 3. Gargleblasters 49 pts. 26,072
• 4. Go Science 33 pts. 26,024
• 5. BIchallenge 22 pts. 25,934
• 6. Marvin's bunch 14 pts. 25,459
• 7. L'Alliance Francophone 8 pts. 25,033
• 8. Beta Folders 5 pts. 24,818
• 9. Australia 3 pts. 24,706
• 10. Void Crushers 2 pts. 24,699

Top soloists

• 1. Aubade01 100 pts. 26,287
• 2. infjamc 96 pts. 26,248
• 3. Nicm25 92 pts. 26,180
• 4. robgee 88 pts. 26,109
• 5. HuubR 84 pts. 26,072
• 6. silent gene 81 pts. 26,024
• 7. spvincent 77 pts. 25,959
• 8. julianfuchs 74 pts. 25,934
• 9. NeLikomSheet 70 pts. 25,911
• 10. georg137 67 pts. 25,909

Comments

[rmoretti]

Information about the objectives in this puzzle. (All objectives give +1000 points when fully satisfied, for a maximum of +10 000.)

• Alter Core - A large bonus for changing up the central five-member-ring with a hydroxyl oxygen. (Click "Show" to highlight the ring at issue.)
• HBond - A large bonus for preserving all the existing hydrogen bonding contacts of the starting ligand. (Click "Show" to highlight the atom needing the hydrogen bond.)
• Bad Groups - Gives a bonus for avoiding groups we're interested in removing, including enol, enamine, thiocarbonyl, hydroxylamines, geminal diols, charged nitrogens, and alpha-beta unsaturated carbonyls. (Click "Show" to highlight groups at issue.)
• Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens.
• Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens.
• Ligand Hydrogen Bond Donors - Keep the number of ligand hbond donors low.
• Molecular Weight - Intended to keep the ligand from getting too big.
• Number of Rotatable Bonds - Intended to keep the ligand from getting too big and floppy.
• Ligand Substructure - Identify areas of the small molecule which aren't very drug-like.
• Synthetic Accessibility - Identify molecules which are likely to be hard to make in the lab.

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.)