2079: VHL ligand design: Round 6

Closed since about 4 years ago

Summary

• Created: December 08, 2021
• Expires: December 15, 2021 at 23:00 UTC
• Max points: 100

Description

Design a small molecule which can bind VHL! This is the sixth 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



We saw some interesting designs in Round 5(b). Round 6 is very similar. We're still asking you to focus on changing the central five-member ring with the attached red oxygen as well as removing the attached amide group, while maintaining the existing hydrogen bonding interactions. Round 6 has a tighter TPSA penalty and a more relaxed cLogP penalty. Drug design is a balancing act, and we hope this new balance between these two competing objectives will be more helpful. We've also made the rotatable bond penalty more stringent -- the center hydroxyl OH is likely to be most useful if it's attached to something like a rigid ring, rather than groups which have rotatable bonds.


You should be able to load existing solutions from Round 5 and Round 5b into this puzzle to further refine them.



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. Contenders 100 pts. 26,076
• 2. Gargleblasters 71 pts. 26,000
• 3. Anthropic Dreams 49 pts. 25,951
• 4. Go Science 33 pts. 25,923
• 5. BIchallenge 22 pts. 25,787
• 6. Ogre's lab 14 pts. 25,622
• 7. Marvin's bunch 8 pts. 25,460
• 8. Australia 5 pts. 25,446
• 9. Beta Folders 3 pts. 25,414
• 10. L'Alliance Francophone 2 pts. 25,264

Top soloists

• 21. spvincent 41 pts. 25,554
• 22. maithra 39 pts. 25,531
• 23. fpc 37 pts. 25,460
• 24. alcor29 35 pts. 25,457
• 25. NinjaGreg 33 pts. 25,453
• 26. AlkiP0Ps 32 pts. 25,446
• 27. Corvac 30 pts. 25,440
• 28. LociOiling 28 pts. 25,414
• 29. fiendish_ghoul 27 pts. 25,411
• 30. Maerlyn138 26 pts. 25,330

Comments

[rmoretti]

Information about the objectives in this puzzle. (All objectives give +1000 points when fully satisfied, for a maximum of +10 000.)

• Alter Core - A large bonus for changing up the central five-member-ring with a hydroxyl oxygen. (Click "Show" to highlight the ring at issue.)
• HBond - A large bonus for preserving all the existing hydrogen bonding contacts of the starting ligand. (Click "Show" to highlight the atom needing the hydrogen bond.)
• 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. (Click "Show" to highlight groups at issue.)
• Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens.
• Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens.
• 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.

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.)

[spvincent]

Finally: a crash that can be reproduced (linux)

1) Load scientist-shared solution ss 24122
2) Select the ligand oxygen h-bonded to Tyrosine 37
3) Also select the carbon bound to that oxygen
4) Try and make it a single bond.

Boom!

[rmoretti]

This crash should be fixed in the Dec 13th devprev release. (Thanks for the reproduction case!)