Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/MIC-UNK-9582b2c5
These designs have three unspecified stereo centers. What is the stereoselectivity of the synthesis startegy you propose?
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I think the idea of merging these structures is good. Nevertheless, I would recommend holding off until we’ve got a better idea of the binding mode for BEN-DND-93268d01-8 and have established that inhibitory activity of ADA-UCB-6c2cb422-1 is maintained when it is annulated to PET-UNK-c9c1e0d8-3 .
I’d expect BEN-DND-93268d01-8 to be predominantly neutral at pH = 7 (the pKa for values for 1,4-dimethylpiperazine and glycine amide are each ~8). I found a couple of relevant crystal structures (HODQUP and UWUJAZ ) in the Cambridge Structural Database and these point to a conformation in which the amide NH of BEN-DND-93268d01-8 eclipses the lone pair of the piperazine nitrogen.
On the second thought i think that this design is wrong, because most probably the dominant isomer would be trans- and so it would be flat. If BEN-DND-93268d01-8 docks the way I think it does piperidine would overlap with, say, p-phenylenediamine from ALP-POS-c59291d4-2, that would mean that N-acetylpiperidine part of that trans-azadecalin would be perpendicular to preferred conformation of piperidine. Either way, conformation of bound BEN-DND-93268d01-8 will be needed to say anything about this molecule
Cis- isomer, on the other hand, won’t be flat so maybe it could bind in right conformation. But I’m not sure.