Submission FRA-DIA-8640f307

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/FRA-DIA-8640f307

@AnthonyA, do these guys look synthetically feasible?

@matteoferla, how does Fragmenstein score these guys? Particular questions:

  • The atoms are meant to map directly from hit to design - does your algorithm figure it out?
  • The protein conformation down in H61/M165/C145 is quite varied for the different inspirations - if you aren’t already, then you need your heuristic to spot which sidechains move, and include them in the things that move and are tracked. (I think… :thinking:)

Compound 1 inspiriation fragments are here:
https://fragalysis.diamond.ac.uk/viewer/react/projects/35/71
And the screen-grab:

Compound 2 (and 3) come from the nitrile of x0305 (and others):
https://fragalysis.diamond.ac.uk/viewer/react/projects/35/72
Screen grab:

Sorry, I did not notice there were two submissions.

Okay. I am sorry to say, but your SMILES are wrong. Your heterocycles don’t come out planar. These are aromatic, because you did not specify the Hydrogen or positive charge.

  • CC(=O)NCCc1c2cc(F)cc(C(CN(Cc3cc(C)on3)C(=O)NC3CC3)c3nnc(C)s3)c2[nH]c1
  • CC(=O)NCCc1c2cc(C#N)cc(C(CN(Cc3cc(C)on3)C(=O)NC3CC3)c3nnc(C)s3)c2[nH]c1
  • CC(=O)NCCc1c2cc(Cl)cc(C(CN(Cc3cc(C)on3)C(=O)NC3CC3)c3nnc(C)s3)c2[nH]c1

Results

name mode ∆∆G comRMSD N_constrained_atoms runtime disregarded
0 FRA-DIA-8640f307-1 none -15.6921 0.88076 38 16.8203 [‘x0305’]
1 FRA-DIA-8640f307-2 none -13.4534 0.886753 37 16.4181 [‘x0305’]
2 FRA-DIA-8640f307-3 none -13.8871 0.889806 37 16.9554 [‘x0305’]

These are minimised, so they work fine:

@mc-robinson, can you update those smiles please.

@AnthonyA, I hadn’t seen until now those minimisations that @matteoferla had run; according to that, these are very happy compounds.
Please let’s discuss how to get them made…

Hi @frankvondelft, @matteoferla, sorry I didn’t see this earlier. This should now be fixed. Just a bit of the reason for why users cannot edit their SMILES directly:

Implementing this is a pain, because once a compound is ordered/made/assayed, we don’t want the identity to change in our system from what was actually ordered/made/assayed. Furthermore, even before that, CDD integration messes up due to the SMILES being different.

I also believe @alphalee said he has routes for these if you want to get them made.