2071: VHL ligand design: Round 4

Closed since over 4 years ago

Summary

• Created: November 17, 2021
• Expires: November 24, 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 to the Small Molecule Design Preset, or

• 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're interested to see if you can fill the void at the center of the pocket, and make hydrogen bonds to the two unsatisfied polars there. (This is the location of the hydroxyproline in Round 1 & Round 2, which we've removed from the starting structure of this round.) The objectives from the previous rounds are back, set up so you'll get a nice bonus if you're able to satisfy the two polars in the center of the pocket. Similar bad groups as before, though they've been adjusted such that remaking the hydroxyproline from Round 1 or 2 (or something similar) won't get you the full bonus.



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. 21,982
• 2. Contenders 71 pts. 21,973
• 3. Anthropic Dreams 49 pts. 21,907
• 4. Gargleblasters 33 pts. 21,883
• 5. Beta Folders 22 pts. 21,735
• 6. Australia 14 pts. 21,496
• 7. Ogre's lab 8 pts. 20,566
• 8. BIchallenge 5 pts. 20,520
• 9. Marvin's bunch 3 pts. 20,357
• 10. L'Alliance Francophone 2 pts. 20,307

Top soloists

• 11. LociOiling 58 pts. 21,735
• 12. Bruno Kestemont 55 pts. 21,734
• 13. grogar7 52 pts. 21,670
• 14. alcor29 49 pts. 21,608
• 15. cjddig 46 pts. 21,601
• 16. infjamc 43 pts. 21,585
• 17. ZeroLeak7 41 pts. 21,565
• 18. silent gene 38 pts. 21,505
• 19. AlkiP0Ps 36 pts. 21,496
• 20. nspc 34 pts. 21,417

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 and the histidine 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. Also rewards avoiding a hydroxyproline-like solution to the HBond filter.
• 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.)