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2085: VHL ligand design: Round 8
Status: Closed


Name: 2085: VHL ligand design: Round 8
Status: Closed
Created: 12/22/2021
Points: 100
Expired: 12/29/2021 - 23:00
Difficulty: Intermediate
Description: Design a small molecule which can bind VHL! This is the eighth 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 7, for Round 8 we've tightened the TPSA objective even further, as well as being more stringent with rotatable bonds. 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.

Categories: Overall, Small Molecule Design

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3Anthropic Dreams26,03458
4Go Science26,00143

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1Aubade01 45 44  26,348100
2Nicm25 45 449  26,34796
3infjamc 33 22 Contenders26,14291
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rmoretti's picture
User offline. Last seen 51 min 18 sec ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Objective Information

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.)

spvincent's picture
User offline. Last seen 2 hours 47 min ago. Offline
Joined: 12/07/2007
Groups: Contenders

The following sequence reproducibly crashes Foldit on Linux: both Main and Devprev.

1) Load scientist-shared solution ss_qs3
2) Select one of the hydrogens on the methyl group at the end of the alkyl chain as shown in screenshot.png (actually I don't think the exact one matters nor does it matter if a carbon is selected instead)
3) Attach an imidazole group from the Fragment selector (doesn't matter which of the four attachment points is used)
4) Wiggle
5) Stop wiggle and Undo twice.
6) Redo step 2.
7) Redo step 3.

Crashes every time

spvincent's picture
User offline. Last seen 2 hours 47 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
Sorry: having trouble

Sorry: having trouble uploading the screenshot: hope the description is sufficient.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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