2088: VHL ligand design: Round 9

Closed since about 4 years ago

Summary

• Created: December 30, 2021
• Expires: January 05, 2022 at 23:00 UTC
• Max points: 100

Description

Design a small molecule which can bind VHL! This is the ninth 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. The puzzle setup is basically the same as Round 8. But for Round 9, the Alter Core objective has been adjusted. It is no longer sufficient to simply break open the center five-member ring. You will need to replace that ring with some other ring system to get the full bonus.



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. 27,865
• 2. Gargleblasters 73 pts. 27,404
• 3. Anthropic Dreams 52 pts. 27,359
• 4. Go Science 36 pts. 27,232
• 5. BIchallenge 24 pts. 26,998
• 6. Beta Folders 16 pts. 26,915
• 7. Australia 10 pts. 25,796
• 8. L'Alliance Francophone 6 pts. 25,711
• 9. Void Crushers 4 pts. 25,581
• 10. Marvin's bunch 2 pts. 25,549

Top soloists

• 1. infjamc 100 pts. 27,850
• 2. Aubade01 95 pts. 27,791
• 3. Nicm25 90 pts. 27,780
• 4. HuubR 85 pts. 27,404
• 5. robgee 80 pts. 27,359
• 6. silent gene 76 pts. 27,224
• 7. gmn 72 pts. 27,193
• 8. spvincent 68 pts. 27,163
• 9. fiendish_ghoul 64 pts. 27,085
• 10. NeLikomSheet 60 pts. 27,034

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 an attached hydroxyl oxygen. You will need to replace the current five-member ring with some other ring system to get the full bonus. (Click "Show" to highlight the ring at issue; "Show" will also highlight the hydroxyl if it needs to be attached to a new ring.)
• 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.)