Submission NIR-THE-5be8b355

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/NIR-THE-5be8b355

Hi @londonir

Attaching sp3 carbon to the amide nitrogen is expected to flip the trans/cis geometric preference of the amide (compare MAT-POS-bb423b95-7 with ADA-UCB-6c2cb422-1).

@pwkenny, interesting point. It looks like we may be able to work the other way around by functionalizing the benzylic alpha-carbon, which would make synthesis easier too.

Hi @mc-robinson, I’d recommend taking a closer look (check reversibility; get crystal structure) at MAT-POS-0c8fa4a7-1. Replacing the benzylic sp3 carbon of ALP-POS-477dc5b7-1 with sp2 carbon will have a significant change in molecular shape and the activity of MAT-POS-0c8fa4a7-1 would be surprising for a non-covalent inhibitor. If MAT-POS-0c8fa4a7-1 does indeed form a covalent bond with the catalytic cysteine then the rigidity of the fused ring system is likely to make this more difficult.

We did try, without success, to get a crystal structure for MAT-POS-0c8fa4a7-1. I’ll need to double check my records but I don’t think there was any obvious reason why.

I’ll run it through the platform again with our new crystal form just to see if anything sticks.

Thanks for the info, Daren, and another possibility is that something adds across the carbon-carbon double bond under assay conditions. That said, I can’t see a concentration response for the fluorescence assay and the concentration responses for the RapidFire assay look flaky.