These designs place a sulfonyl group within the saturated ring of the P2 group where it will be relatively well exposed to solvent (there is the possibility that one of the sulfonyl oxygen atoms may accept a hydrogen bond from the Q189 side chain amide although I don’t expect this to affect affinity to a significant extent). I would anticipate that the designed inhibitors will be more soluble than their chromane equivalents and the presence of the sulfonyl would be expected to provide some protection against metabolism for the adjacent methylenes. I have generated the designs combinatorially (2 x 2 x 2: chiral center substituted with MeO; F at C6 of isoquinoline; F on P2 aromatic ring) although I’d recommend testing the idea initially with design 1 (no Fs or MeO) and design 5 (MeO but no Fs). The puckering of the saturated ring depends on whether the chiral center is substituted with MeO which means that both design 1 and design 5 would need to be synthesized in order to test the idea properly.
Protein-ligand complexes were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at their crystallographic positions). The X11612 A chain was used for modelling designs 1-4 and the P0157 A chain was used for modelling designs 5-8. The PDB file associated with this submission contains the following:  X11612 A chain  X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-6] Designs 1-4  P0157 A chain  P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [9-12] Designs 5-8