Hi @edgriffen SAM-UNK-2684b532-12 is unremarkable in the fluorescence assay although the 3-amino, 4-trifluoropyridine does look like an excellent leaving group. I would not be surprised if the activity of SAM-UNK-2684b532-12 (if genuine) is due to it functioning as an acylating agent. I believe that the activity of ALP-POS-c59291d4-5 may be due to this type of behavior.
Your absolutely right about ALP-POS-c59291d4-5 we had a crystal structure and you get the acylated cysteine. We should get a structure of SAM-UNK-2684b532-12 before synthesis commences so we can make the call then - thanks for calling it out.
Is it apt, at this stage, to consider a transition state inhibitor? If the C=O is “under attack” by SH, maybe a S-oxide or B(OH)2 or the like could be inserted in place of the C=O? Earlier, less elaborated analogues are here:
https://covid.postera.ai/covid/submissions/7a6e29a5-99ab-444e-b240-5af3701e431a