puzzle picture
2068: VHL ligand design: Round 3
Status: Closed

Summary

Name: 2068: VHL ligand design: Round 3
Status: Closed
Created: 11/10/2021
Points: 100
Expired: 11/17/2021 - 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:
  • 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've cut back on the size of the starting compound, to encourage players to change up the core of the ligand. Extend the starting ligand into the rest of the pocket, filling in voids and making hydrogen bonds.

There's an HBond objective which should give you a big bonus if you're able to make a hydrogen bond to the serine in the middle of the protein. We've also added a Buried Unsat objective to keep potential hydrogen bonders from getting unsatisfied. The objectives from the previous rounds are present again, with slightly adjusted thresholds. Added to the "Bad Groups" objectives are the hydroxylamine, geminal diol, alpha-beta unsaturated carbonyl and charged (four-bonded) nitrogen 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

Top Groups

RankGroupScorePoints
1Go Science22,078100
2Ogre's lab21,98573
3Contenders21,85052
4Gargleblasters21,82236
5Anthropic Dreams21,81324

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1Aubade01 68 46  22,212100
2ichwilldiesennamen 27 17 Go Science22,07796
3Nicm25 68 66  22,04191
4Borets 68 41 Ogre's lab21,98586
5Bletchley Park 10 19 Contenders21,85082


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Comments

rmoretti's picture
User offline. Last seen 1 hour 5 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 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.
  • 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.)

alcor29's picture
User offline. Last seen 6 hours 59 min ago. Offline
Joined: 11/16/2012
bonds to protein?

Guessing from your view settings, making bonds from the ligand to the protein is not important?

alcor29's picture
User offline. Last seen 6 hours 59 min ago. Offline
Joined: 11/16/2012
nvm

I guess the sheet bonds will take care of it.

alcor29's picture
User offline. Last seen 6 hours 59 min ago. Offline
Joined: 11/16/2012
and.....

there's the serine you mentioned. Duh.

rmoretti's picture
User offline. Last seen 1 hour 5 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Serine sidechain to ligand hbond.

In case it's still unclear, the Objective should pick up the hydrogen bond between the serine sidechain to the ligand. (There's some existing hydrogen bonds between that serine and other protein residues, but the bonus should be specific to forming a new hydrogen bond to that serine sidechain.)

To locate the serine, you can click the "Show" of the HBond objective. That should label the sidechain hydroxyl which needs the hbond with a red glow. (Look at the bottom middle of the pocket.)

Aubade01's picture
User offline. Last seen 2 days 10 hours ago. Offline
Joined: 10/12/2013
Groups: None
Client Crash

Adding a nitrogen in close proximity to the protein bound imidazole causes the client to crash and disappear.
Windows 10. Crash repeated.

>>>>> Aubade00/01

rmoretti's picture
User offline. Last seen 1 hour 5 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Share with scientists?

If you could share with scientists the particular structure which causes the crash, that would help. (It's often the details about the particular structure you generated which results in issues.)

Aubade01's picture
User offline. Last seen 2 days 10 hours ago. Offline
Joined: 10/12/2013
Groups: None
CRASH STRUCTURE

This structure has been uploaded.

The tertiary methyl group on the left side has a methyl proximate to the imidazole. Substituting the right and downward hydrogen with nitrogen gives a crash on my system.

>>>>> Aubade00/01

alcor29's picture
User offline. Last seen 6 hours 59 min ago. Offline
Joined: 11/16/2012
Crashy

Very crashy again. 3 or 4 times already this morning. Hard to work this way. Will allow one more crash and then done with 2068. Sorry can't find log since running multiple clients.

(It would be nice to run separate logs for each client. )

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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