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2059: VHL ligand design: Round 1
Status: Closed

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rmoretti's picture
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Joined: 01/15/2010
Groups: Foldit Staff
Objective Information

Information about the objectives in this puzzle. (All objectives give +1000 points when fully satisfied.)

  • Amide Penalty - Fewer amides reduce how "peptide like" the molecule is.
  • 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.

Most objectives have a "Show" button which should highlight areas of concern in red.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
Amide penalty (or bonus)

The amide penalty seems to be only 2.5 points per amide.

There are three amides when the puzzle starts. If you remove one of the oxygens from those amides, the amide penalty score changes from 992.25 to 995.

Zapping two more oxygens gets you to the full 1000 point bonus.

Is this as intended? It seems like a deduction of 25 or even 250 points would be more typical.

cas0362's picture
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Joined: 08/15/2017
Groups: BIchallenge
Agreed

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).

rmoretti's picture
User offline. Last seen 1 day 5 hours ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
It is intended, for the first round

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.

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