2091: VHL ligand design: Round 10

Closed since about 4 years ago

Summary

• Created: January 05, 2022
• Expires: January 12, 2022 at 23:00 UTC
• Max points: 100

Description

Design a small molecule which can bind VHL! This is the tenth (and final!) 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 9. For Round 10, we still want you to replace the center five-member ring to some other ring system, but have adjusted the penalty for breaking-but-not-reforming the center ring. We've also adjusted the rotatable bond bonus and made the TPSA bonus more stringent.



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. 28,862
• 2. Gargleblasters 71 pts. 28,190
• 3. Marvin's bunch 49 pts. 27,920
• 4. Anthropic Dreams 33 pts. 27,834
• 5. Go Science 22 pts. 27,711
• 6. BIchallenge 14 pts. 27,576
• 7. Beta Folders 8 pts. 27,379
• 8. Ogre's lab 5 pts. 26,661
• 9. Australia 3 pts. 26,420
• 10. Void Crushers 2 pts. 26,277

Top soloists

• 1. infjamc 100 pts. 28,815
• 2. Aubade01 96 pts. 28,520
• 3. Nicm25 91 pts. 28,491
• 4. HuubR 87 pts. 28,190
• 5. guineapig 83 pts. 28,017
• 6. fpc 79 pts. 27,920
• 7. robgee 75 pts. 27,816
• 8. gmn 72 pts. 27,713
• 9. silent gene 68 pts. 27,711
• 10. Bruno Kestemont 65 pts. 27,664

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.)

[rmoretti]

For those who are curious, this will be the last puzzle in the VHL ligand design series (at least for a while).

When this puzzle closes, we'll be taking the results from all the rounds and analyzing them closely with our collaborators at Boehringer Ingelheim. If any of the compounds pass BI's quality thresholds, they should be synthesized and tested later this year.

We will keep you posted about the results from the analysis, and which compounds (if any) are going to be synthesized.

Additional ligand design puzzles are planned, but they'll be taking a hiatus while we analyze the results from this series and update the tools to make it easier for you to design quality compounds.

[spvincent]

I find it's hard to work around all these objectives. Bad groups, Ligand Substructures, and Synthetic Accessibility objective filters all seem to cover broadly similar ground, yet the penalties feel arbitrary and somewhat capricious. For example changing a methyl group to an ethyl group, which doesn't look as if it would present a great synthetic challenge, sometimes results in a Synthetic Accessibility penalty of 400-odd and sometimes not: it's very hard to figure out why. Also any Synthetic Accessibility penalty is invariably between 400 and 500: in the real world there can't be such a sharp divide between what is synthetically possible and what is not.

I've tried several times to introduce things such as trifluoromethyl groups: they seem to occur quite frequently in drug molecules but in these puzzles they invariably incur a Synthetic Accessibility penalty.