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2059: VHL ligand design: Round 1
Status: Closed

Summary

Name: 2059: VHL ligand design: Round 1
Status: Closed
Created: 10/20/2021
Points: 100
Expired: 10/27/2021 - 23:00
Difficulty: Intermediate
Description: Design a small molecule which can bind VHL! This is the first 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.

For this puzzle, we're staring you off with a known VHL binder, and are asking you to make it better. In particular, we'd like people to make it look less like a peptide. The current ligand has a number of amide groups. We think that removing these groups would make it work even better for eventual use in PROTACs. To that end, we have an Amide Penalty objective which gives a bonus for having fewer amides. We're also hoping people pay attention to TPSA and Hydrogen Bond Donors, which are two other important criteria.

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)

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: Small Molecule Design

Top Groups

RankGroupScorePoints
1Anthropic Dreams20,080100
2Contenders19,65674
3Marvin's bunch19,43254
4BIchallenge19,42538
5Gargleblasters19,32927

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1Nicm25 70 68  20,209100
2gmn 9 8 Anthropic Dreams20,07796
3grogar7 33 2 Anthropic Dreams20,02691
4Aubade01 70 43  19,84887
5Bletchley Park 10 20 Contenders19,65683


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Comments

rmoretti's picture
User offline. Last seen 1 day 4 hours 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.)

  • Amide Penalty - Fewer amides reduce how "peptide like" the molecule is.
  • 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.

Joined: 12/27/2012
Groups: Beta Folders
Amide penalty (or bonus)

The amide penalty seems to be only 2.5 points per amide.

There are three amides when the puzzle starts. If you remove one of the oxygens from those amides, the amide penalty score changes from 992.25 to 995.

Zapping two more oxygens gets you to the full 1000 point bonus.

Is this as intended? It seems like a deduction of 25 or even 250 points would be more typical.

cas0362's picture
User offline. Last seen 6 days 14 hours ago. Offline
Joined: 08/15/2017
Groups: BIchallenge
Agreed

Larger benefit associated with amide removal would make sense in context of providing diverse, potentially more useful E3 ligase binders for use in PROTACS (e.g. with better potential for good DMPK properties).

rmoretti's picture
User offline. Last seen 1 day 4 hours ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
It is intended, for the first round

Yeah, where we set the levels for the bonuses is something we'll have to figure out. The plan is to run several rounds of the VHL ligand design puzzles, with different settings for the bonuses. We'll take a look at the structures coming out of the first round and see if we need to adjust things.

One consideration is that we don't necessarily want to encourage people to make poor binders in the goal to remove amides. A deduction of 250 points would likely promote people to remove all the amides, even if that makes a poor binder. We need to balance the penalties to strike the right trade-off. With later rounds we'll be able to dial that in better, but for the first round we tried to be somewhat conservative.

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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