puzzle picture
2139: KLHDC2 ligand design: Round 2
Status: Closed

Summary

Name: 2139: KLHDC2 ligand design: Round 2
Status: Closed
Created: 04/27/2022
Points: 100
Expired: 05/04/2022 - 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).

Since the first round, we've added two water molecules which are taking up space in the pocket (one which has a hydrogen bonding opportunity). We've also increased the stringency of the TPSA and Bad Groups objectives.

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
1Contenders23,587100
2Anthropic Dreams23,04268
3BIchallenge22,61944
4Go Science22,35627
5Gargleblasters22,15616

Top Evolvers

Top Soloists

RankPlayerGroupScorePoints
1Aubade01 46 42  23,655100
2Bletchley Park 8 8 Contenders23,58794
3ucad 46 45  23,35189
4Sandrix72 46 17  23,14583
5gmn 4 5 Anthropic Dreams23,02878


Need this puzzle? Log in to download.  

Comments

rmoretti's picture
User offline. Last seen 1 hour 41 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 +12 000. 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.)
  • 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.)
spvincent's picture
User offline. Last seen 2 hours 50 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
This crashes all the time, to

This crashes all the time, to the extent that it's unplayable. Funny: the previous version of Foldit that others found unstable when playing the last ligand design puzzle worked just fine for me: now things are reversed. Linux/main.

Scientist-shared a couple of structures with steps needed to cause a crash (named test_pre and test)

User login
Download links:
  Windows    OSX    Linux  
Windows
(7/8/10)
OSX
(10.12 or later)
Linux
(64-bit)

Are you new to Foldit? Click here.

Are you a student? Click here.

Are you an educator? Click here.
Social Media


Search
Only search fold.it
Other Games: Mozak
Recommend Foldit
Topics
Top New Users
Sitemap

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