2068: VHL ligand design: Round 3

Closed since over 4 years ago

Summary

• Created: November 10, 2021
• Expires: November 17, 2021 at 23:00 UTC
• Max points: 100

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.

Top groups

• 1. Go Science 100 pts. 22,079
• 2. Ogre's lab 73 pts. 21,986
• 3. Contenders 52 pts. 21,850
• 4. Gargleblasters 36 pts. 21,822
• 5. Anthropic Dreams 24 pts. 21,813
• 6. AlphaFold 16 pts. 21,768
• 7. Marvin's bunch 10 pts. 21,520
• 8. Australia 6 pts. 21,321
• 9. BIchallenge 4 pts. 20,465
• 10. Beta Folders 2 pts. 20,425

Top evolvers

• 1. toshiue 100 pts. 22,079
• 2. Bruno Kestemont 68 pts. 22,078
• 3. Bletchley Park 44 pts. 21,850
• 4. Galaxie 27 pts. 21,813
• 5. alcor29 16 pts. 21,771
• 6. gmn 9 pts. 21,708
• 7. robgee 5 pts. 21,572
• 8. phi16 3 pts. 21,572
• 9. fpc 1 pt. 21,520
• 10. puxatudo 1 pt. 21,452

Comments

[rmoretti]

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.
</ul> 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]

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

[alcor29]

I guess the sheet bonds will take care of it.

[alcor29]

there's the serine you mentioned. Duh.

[Aubade01]

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]

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.)

[rmoretti]

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]

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]

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. )