2322: KLHDC2 the Next Level: Round 5

Closed since over 2 years ago

Summary

• Created: June 30, 2023
• Expires: July 07, 2023 at 23:00 UTC
• Max points: 100

Description

Foldit players have discovered a small molecule fragment which binds well to KLHDC2. Take this starting fragment and expand upon it.

For Round 5, we're checking how useful the compound library settings are. We've heard concerns about the compound library being liming, and for this round we're giving you free reign -- no Compound Library objective and no Compound Library panel. See if you can come up with novel compounds, without the concern about library availability. Note that we'll still likely be experimentally testing only compounds which are commercially available, but we're seeing if leaving off the Compound Library tools and only doing the commercially available compound search as a post-processing step allows players to more easily explore chemical space and find interesting compounds.

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

This is a project in collaboration with Boehringer Ingelheim. 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.

Top groups

• 1. Go Science 100 pts. 24,389
• 2. Contenders 68 pts. 23,963
• 3. Anthropic Dreams 44 pts. 23,962
• 4. Gargleblasters 27 pts. 23,779
• 5. Australia 16 pts. 23,443
• 6. VeFold 9 pts. 23,243
• 7. BIchallenge 5 pts. 22,918
• 8. AlphaFold 3 pts. 22,819
• 9. Marvin's bunch 1 pt. 22,498
• 10. L'Alliance Francophone 1 pt. 22,486

Top soloists

• 1. Sandrix72 100 pts. 24,389
• 2. pr0tfold 94 pts. 24,303
• 3. Bletchley Park 87 pts. 23,963
• 4. gmn 81 pts. 23,962
• 5. nspc 76 pts. 23,910
• 6. HuubR 70 pts. 23,779
• 7. Bruno Kestemont 65 pts. 23,776
• 8. blazegeek 60 pts. 23,751
• 9. rosie4loop 56 pts. 23,728
• 10. grogar7 52 pts. 23,723

Comments

[rmoretti]

Objectives

Maximum bonus: +12 000

Core (max +1000)
Does the small molecule design contain the starting molecule as a substructure, or the essential features from one of the known binders?

HBond (max +1000)
Is the ligand making hydrogen bonds to the same groups on the protein as the starting structure does? (Show highlights the groups on the protein which need to be hydrogen bonded.)

Ligand Hydrophobic Interaction (max +1000)
Is the ligand making good hydrophobic packing interactions with specific residues? (Show highlights the residues on the protein which should be involved in the interaction.)

Torsion Quality (max +1000)
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 (max +1000)
Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show highlights rotatable bonds.)

Ligand TPSA (max +1000)
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 (max +1000)
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 (max +1000)
Keep the number of ligand hbond donors low. (Show highlights atoms which are counted as hydrogen bond donors.)</li>

Bad Groups (max +1000)
Gives a bonus for avoiding groups that interfere with assays, or which are far from the compounds in the library. (Show highlights groups at issue.)

Element Counts (max +1000)
Gives a bonus for not having too many of particular elements. (Show highlights atoms which are over represented.)

Molecular Weight (max +1000)
Keeps the ligand a reasonable size.

Synthetic Accessibility (max +1000)
Keeps the ligand from going too far from the compounds in the library. (Show highlights parts of the molecule at issue.)

[nspc]

since round 2, Compound library was more easy to use. But yea, it can be interesting to test without for this round ^^

[rosie4loop]

I think the hydrophobic interaction bonus in round 4 was doing a good job to help getting out of the local minima of high-scoring seed compounds while keeping the library bonus. In round 3, a library search of the seed compound giving scores that was hard to beat with a new design, but from round 4 onwards the hydrophobic interaction bonus greatly lowered the barrier in evolving the compounds.

It'd be interesting to see if removing the library panel would lead to more adventurous exploration of chemical space. Many players who've played the previous rounds should have their mind trained by library hits already, and using the virtual library in their brain (or getting inspiration from external source). These can be either a guide of what a realistic compound is like, or a restriction of creativity. It'd be interesting to know which statement better represent the role of the library.

Another way to check the use of library would be keeping the library panel for inspiration while reducing or removing the library bonus. Allow slight modification of compounds hits for affinity, and provide a guide of what is chemically feasible.

But in my opinion, all of the following statements sound interesting for me

• "player without medical background add a [methyl/amino/hydroxyl/…] group to a library compound results in 10-fold affinity"
• "player without medical background designing novel compounds guided by objectives of what is chemically feasible"
• "player without medical background selecting potent library compounds, which is falsely rejected by major virtual screening protocols"