puzzle picture
2151: KLHDC2 ligand design: Round 6
Status: Closed

Summary

Name: 2151: KLHDC2 ligand design: Round 6
Status: Closed
Created: 05/25/2022
Points: 100
Expired: 06/01/2022 - 23:00
Difficulty: Intermediate
Description: Design a small molecule which can bind to KLHDC2! We don't want you to modify the protein, but instead use the small molecule design tools to build new small molecules which fit into the KLHDC2 binding pocket.

Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.

The starting ligand is a peptide which binds to KLHDC2. We're interested in designs which make it less peptide-like and with better TPSA, but which keep the carboxylate interaction and the hydrophobic pocket interaction. See the blog post for more background information, and pay attention to the various objectives. Note that as the KLHDC2 domain is a bit large, we've trimmed the protein down to just the pocket (this shouldn't affect the prediction of compound binding interactions).

The major change since the previous round, is the addition of two more water molecules which are making contact with the starting ligand. Along with that, there's a new HBond objective which gives a bonus if you continue to make waters and sidechains the starting molecule does. (Click "show" to see which atoms to make bonds to -- note that you don't need all of them to get the bonus.) We've also further increased the stringency of the clogP objective, but backed off a bit on the TPSA objective. Positively charged nitrogens (ones with four bonds) are also being penalizes more heavily.

This is a project in collaboration with Boehringer Ingelheim & Oxford University. Boehringer Ingelheim & Oxford have committed to help evaluate and test the molecules which Foldit players have designed. The structures of all compounds created as part of the collaboration puzzles as well as any experimental results from testing them will be made publicly available. 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 Science23,269100
2Contenders23,06168
3Anthropic Dreams22,60744
4BIchallenge22,00727
5Gargleblasters20,98016

Top Evolvers

RankPlayerGroupScorePoints
1maithra 6 22 Contenders22,980100
2guineapig 16 12  22,69295
3gmn 3 4 Anthropic Dreams22,60789
4Galaxie 1 2 Anthropic Dreams22,60484
5LociOiling 2 1 Anthropic Dreams22,59279

Top Soloists

RankPlayerGroupScorePoints
1Sandrix72 8 6  23,269100
2ZeroLeak7 36 16 Go Science23,23395
3Bletchley Park 9 14 Contenders23,06189
4Aubade01 51 20  22,82184
5guineapig 16 12  22,73579


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Comments

rmoretti's picture
User offline. Last seen 18 hours 6 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Objective Information

There's a number of objectives. Most of them are there to keep the molecule going "too far" outside the range of acceptable parameters for drugs.

All objectives give +1000 points when fully satisfied, for a maximum of +13 000. 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, so it's not recommended to keep Show on at all times.

  • Carboxylate Interaction - A bonus for keeping the hydrogen bonds the existing carboxylate is making. (Show highlights the protein atoms you need to make the hydrogen bonds to.)
  • Ligand Hydrophobic Interaction - A bonus for keeping a hydrophobic interaction between the ligand and the protein. (Show highlights the protein residues the ligand should contact.)
  • HBond - A bonus for keeping existing hydrogen bonding interactions. (Show highlights the atoms to make hydrogen bonds to.) There are seven potential hydrogen bonds, you only need five to get the bonus.
  • Peptide - Penalizes the formation of peptide-backbone-like groups. (Show highlights which parts of the ligand should be changed.)
  • Torsion Quality - Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)
  • Number of Rotatable Bonds - Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show higlights rotatable bonds.)
  • Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)
  • Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)
  • Ligand Hydrogen Bond Donors - Keep the number of ligand hbond donors low. (Show highlights atoms contributing to higher cLogP.)
  • Bad Groups - Gives a bonus for avoiding groups that aren't very drug-like, including enol, enamine, thiocarbonyl, hydroxylamines, geminal diols, alpha-beta unsaturated carbonyls, aliphatic alkanes, aliphatic alkenes, aliphatic ethers and others. (Show highlights groups at issue.)
  • Element Counts - Limits certain element numbers: Desired P=0, S<=1, I<=1, Br<=1, Cl<=4, F<=4, N<=5 (Show highlights atoms of elements exceeding count.)
  • Molecular Weight - Intended to keep the ligand from getting too big.
  • Synthetic Accessibility - Identify molecules which are likely to be hard to make in the lab. (Show highlights regions of the molecule contributing to difficult synthesis.)
Joined: 12/06/2008
Groups: Contenders
Why does wiggle do nothing?

Why does wiggle do nothing on this puzzle? The only way I can get this ligand to move is to use the "3" multi-arrow button.

rmoretti's picture
User offline. Last seen 18 hours 6 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Saturated?

From my double checking, wiggle should be allowing to the ligand to optimize.

That said, given that the "moveable" parts of this puzzle are very limited (just the ligand), it's rather easy for wiggle to "saturate" -- that is, for it to reach a local maximum of the score and then just stop. Without knowing more, that's my guess as to what you're seeing. The ligand doesn't want to move because it's already found the best structure it can under the optimization approach wiggle uses.

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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