Design a small molecule which can bind VHL! This is the first 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.
For this puzzle, we're staring you off with a known VHL binder, and are asking you to make it better. In particular, we'd like people to make it look less like a peptide. The current ligand has a number of amide groups. We think that removing these groups would make it work even better for eventual use in PROTACs. To that end, we have an Amide Penalty objective which gives a bonus for having fewer amides. We're also hoping people pay attention to TPSA and Hydrogen Bond Donors, which are two other important criteria.
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)
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.
Larger benefit associated with amide removal would make sense in context of providing diverse, potentially more useful E3 ligase binders for use in PROTACS (e.g. with better potential for good DMPK properties).
Yeah, where we set the levels for the bonuses is something we'll have to figure out. The plan is to run several rounds of the VHL ligand design puzzles, with different settings for the bonuses. We'll take a look at the structures coming out of the first round and see if we need to adjust things.
One consideration is that we don't necessarily want to encourage people to make poor binders in the goal to remove amides. A deduction of 250 points would likely promote people to remove all the amides, even if that makes a poor binder. We need to balance the penalties to strike the right trade-off. With later rounds we'll be able to dial that in better, but for the first round we tried to be somewhat conservative.
