Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/EDJ-MED-8bb691af
Hi @edgriffen
The ligand desolvation penalty argument only really applies when a polar ligand surface is in contact with non-polar protein surface. Removal of a polar ligand that is hydrogen bonded to a polar protein creates a mismatch between polar and non-polar surface (likely to reduce both affinity and aqueous solubiity). I’d expect removal of both carbonyls to increase the hydrogen bond basicity of the isoquinoline nitrogen although I’d also anticipate substantial collateral damage. First, it will be more difficult for the isoquinoline ring to get out of coplanarity with respect to the pyrrolidine ring to where it needs to be in order to interact with the S1 subsite. Second, dialkylamino is more electron-releasing than amido which means that removal of both carbonyls is likely to increase the isoquinoline electron density (I would anticipate this will exacerbate metabolic any instability problems associated with isoquinoline).
In case it’s helpful, imide carbonyls look more like ketone carbonyls.