Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/b2d83456-e4d0-4e2b-9117-b154002b1beb
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Will comment on more tomorrow, but just at an initial look, I think PAT-UNK-b2d-1 may be worth ordering since it is readily available in Enamine’s screening library
Note that these very similar compounds are also available in either the screening library or real space, so the compound is ripe for further testing if it looks promising.
Hello,
please note x0692, which was used as inspiration, was a covalent hit. It would be wise to change the design containing a N-acetyl piperazine to N-chloroacetyl piperazine. I wrote a similar post on a design by Nimesh Mistry.
I think this should be noted as a general caveat. Any design should be cross-checked against the covalents list to make sure an electrophile is added where appropriate.
Best Regards
Paul Gehrtz
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Thanks, Paul. I will try to start coding up an automatic check, and get back to you when it’s cross-checked.
Yes thanks Paul for noticing. I guess it will happen a lot; the structures on fragalysis dont make it obvious that there is a covalent bound between the cys145 and the fragments.
@mc-robinson: the check is for every smile that show a methylamide. Check whether the reference is from a covalent structure, if so add Cl to smile.
Do you want me to give you the list of covalent hist?
Hi, we are on the same train of thought! I actually just made the list myself. Will update the other thread of purchase-able compounds. Not sure if the fix will be quite that simple in some of the cases unfortunately.
Yes but if in doubt you can ask. On the list you sent this morning, only one was from a covalent, the other one with a voluntary methylamide
Hmm ok, so the method of just looking for a covalent fragment “inspiring” the design seems to be bringing up too many false positives – if it was just one.
Hello,
thanks for taking care of this issue. For now, I will try to make a case by case check.
Further suspects: JAV-UNI-450, KIM-UNI-2ee, KIM-UNI-7d1
Best
Paul
Hi Paul,
Thanks for your help on this!
For this compound, for ease of speed, the N-chloroacetyl piperazine unfortunately moves us out of Real Space, so a bit longer synthesis, though still probably worth doing.
Note that these are available in Real Space:
I feel like we should try to conserve the design of the submitter:
The first analogue is a para substitution which is probably not wanted
The second too with a different warhead that adds a carbon
The third one is a different warhead too (unknown reactivity) and a gem methyl added which will change the geometry quite a bit.
BUT: Nir wanted to talk to enamine for high throghput addition of warhead and it might be that also not on the database, enamine can easily make them, and this one in particular
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Yes, fair. I definitely think we should try to maintain the original design, but I guess it is good to also follow up with options if the syntheses become prohibitive. In this case, that definitely shouldn’t be so.