Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/PET-UNK-bbe8d7ff
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Hi Matt @mc-robinson
Looks like this compound didn’t show any activity in the assay. Nevertheless, I think that it would be worth trying to get a crystal structure and I’ll include Frank @frankvondelft in the discussion. As discussed previously, substitution of the amide NH with sp3 carbon is likely to invert the amide geometrical preference away from trans (as in the bound ligand) to cis. The two questions that a crystal structure would address are (1) does a covalent bond form between the catalytic cysteine and the carbon of the nitrile warhead? (2) Does the covalent bond compromise geometry of interactions of pyridine nitrogen and carbonyl oxygen with protein? Looks like a structure (x11041) has been determined for the N-methyl analog of the parent compound.
There are other options for presenting a reversible warhead to the catalytic cysteine. However, the synthesis is likely to be more involved and a crystal structure for the existing compound would provide guidance as to how (or even whether) to proceed.
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