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2071: VHL ligand design: Round 4
Status: Closed

Summary

Name: 2071: VHL ligand design: Round 4
Status: Closed
Created: 11/17/2021
Points: 100
Expired: 11/24/2021 - 23:00
Difficulty: Intermediate
Description: Design a small molecule which can bind VHL! This is the third 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, or
  • Set Color: Score/Hydro+CPK
  • Set View Protein: Binding Site or Cartoon Ligand
  • Turn on: Show Clashes, Show Voids, Show bonds (non-protein), Show bondable atoms
  • Turn off: Show exposed, Show bonds (sheet), Show bonds (helix), Show bonds (loop), Show bonds (sidechain)

For this round, we're interested to see if you can fill the void at the center of the pocket, and make hydrogen bonds to the two unsatisfied polars there. (This is the location of the hydroxyproline in Round 1 & Round 2, which we've removed from the starting structure of this round.) The objectives from the previous rounds are back, set up so you'll get a nice bonus if you're able to satisfy the two polars in the center of the pocket. Similar bad groups as before, though they've been adjusted such that remaking the hydroxyproline from Round 1 or 2 (or something similar) won't get you 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.

Categories: Overall, Small Molecule Design

Top Groups

RankGroupScorePoints
1Go Science21,982100
2Contenders21,97371
3Anthropic Dreams21,90749
4Gargleblasters21,88333
5Beta Folders21,73522

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1Aubade01 70 43  22,291100
2Nicm25 70 68  22,12095
3ichwilldiesennamen 27 19 Go Science21,98291
4fiendish_ghoul 70 13  21,94886
5Galaxie 3 3 Anthropic Dreams21,90681


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rmoretti's picture
User offline. Last seen 2 hours 39 min 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.)

  • HBond - A large bonus for making a hydrogen bond to the serine and the histidine in the center of the pocket. (Click "Show" to highlight the atom needing the hydrogen bond.)
  • Buried Unsats - Penalizes polar atoms that cannot make hydrogen bonds
  • 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. Also rewards avoiding a hydroxyproline-like solution to the HBond filter.
  • Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic
  • Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low.
  • 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.)

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, Boehringer Ingelheim, RosettaCommons