Last night on stream I had noticed that whenever I accidentally created a Michael Acceptor in my molecule my score shot down at least 6000 points or so. Is there an undocumented toxicophore detector in the SMD puzzles? If so that's super neat; I was just thinking about how it might be easy to overlook a known toxicophoric structure in hand-modification of lead molecules in my computational drug design class.
I ended up with a "likely unsynthesizable" penalty, -6000 points, when I tried to build Darunavir, (DRV, PDB O17).
Unfortunately, I wasn't watching the score, so I'm not sure what part caused the problem.
Darunavir has two stacked rings at one end, kind of halfway to a Bucky ball, and you can actually build it in Foldit.
I didn't see an unsynthesizable penalty in my conditions tab. See below. I have the structure of a Michael Acceptor from a slide in one of my classes, and you can see I've replicated one in my molecule inadvertently with the amine group. For comparison, I've also uploaded a screenshot of my best where the double bond is fully substituted, and there isn't a second electron withdrawing group (the ketone); the mechanism for the Michael reaction cannot proceed, and the toxicophore is rendered harmless. As you can see, no changes in the filter for synthesizability. And yet, 3000 points. I'm willing to bet that's not from conformational analysis, and in the score breakdown, it seems to come from the Ideality subsection.
This is a fantastic web resource on reducing problems with pre-clinical drug candidates: https://www.cambridgemedchemconsulting.com/resources/ Might I recommend cyclizing that cyclopentane ketone to the nitrogen making a heterocyclic ring system?
https://en.wikipedia.org/wiki/Toxicophore says:
A toxicophore is a chemical structure or a portion of a structure (e.g., a functional group) that is related to the toxic properties of a chemical. Toxicophores can act directly (e.g., dioxins) or can require metabolic activation (e.g., tobacco-specific nitrosamines).
Unfortunately I was taking advantage of the twin H-bond donors of the amine and I just tried that and losing out on it results in too much of a score loss. Great resource though, I was actually building semi-blindly from scratch this time around and if I was gonna take the cookie cutter rational drug design approach I would certainly use resources like those; I just wanted to see how far I could get with raw intuition and in-game cues, as is my style with what a lot of Foldit puzzles actually.
We don't have toxicophore or "bad substructure" tests present in the small molecule design puzzles yet. It's something we're looking into, but nothing that's active yet. (We're hoping to get some more information about the sorts of edge-cases Foldit players like to come up with, first - e.g. what's the "megahelix" for small molecule design.)
If the score penalty is coming from the "Ideality" subsection of the score, then the issue is not the toxicophore, but internal strain in the geometry of the ligand. While a global wiggle should reduce this somewhat, a ligand-specific wiggle can do a much better job. If you select just the ligand and do a wiggle (either in selection mode or through the right-click pie menu in original mode), it should do a slightly different wiggle approach which should do a better job in removing those ideality issues for designed ligands.
The MMFF wiggle (either in selection mode or from the right-click pie menu) should also greatly help with ideality issues, though as it's working with a different energy function than the normal wiggle, there's a chance an MMFF wiggle will decrease your score slightly.
It wasn't immediately obvious, but this actually really helped out with score gains. Thanks for the clarification.
I found the MMFF wiggle button in the selection interface.
It appeared as a button labeled "M" when I selected just
the ligand. When I selected the ligand plus parts of the
protein, this button disappeared. Is it possible to do
MMFF wiggle on more than just the ligand?
In the original interface, why not put the MMFF wiggle
button in the Actions menu along with all the other
wiggle buttons?
Are there hot-keys or LUA functions for MMFF wiggle?
I like S0ckrates' tips
(like Lipinski's Rule of 5 in #18)
for designing small molecules at:
https://fold.it/portal/node/2005231#comment-36784
Perhaps something like Lipinski's Rule of 5
could be built into Foldit.