Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/EDJ-MED-c8e7a002
Hi Ed @edgriffen
As noted for a related submission, the more stable tautomer for indazoles typically places NH next to the ring fuson.
Existing SAR suggests that replacing the replacing the heterocyclic ring of isoquinoline with a 5-membered ring leads to about an order of magnitude loss of potency. I interpret this in terms of the geometry of the hydrogen bond (HB) that the aza nitrogen accepts from H163. It is conceivable that aza substitution adjacent to the HB acceptor nitrogen will help with the HB geometry issue for the 5-membered ring and I have submitted a design to test this hypothesis. As far as I can see, aza-substitution of isoquinoline always results in loss of potency and I am not aware of any crystal structures in which a P1 substituent donates a hydrogen bond to the protein.
The tautomer of the the H163 sidechain can, in principle, ‘flip’ although I consider this possibility unlikely. You could explore this possibility using indazole or even indole as the P1 heterocycle.