The first of these designs is the dimethyl amide of EDG-MED-4c68219f-12 and this can be seen as the structural prototype for a series of tertiary amides (another member of this series is the azetidine amide CHO-MSK-5891c1ff-10 which is currently being synthesized). Although bringing the face of the amide group into contact with the molecular surface of the protein is unlikely to bury the carbonyl oxygen, it is possible that its solvation will still be compromised. The last 5 designs in the submission are azoles which replace the carbonyl oxygen of the amide with a weaker hydrogen bond acceptor. Additionally, rotation around the CH2-azole bond is freer than around the corresponding CH2-amide bond of CHO-MSK-5891c1ff-10 (this may allow the sidechain amide of N142 to donate a hydrogen bond to the ligand). The azoles may be more metabolically stable than the amides. My recommendation would be synthesize designs 1 (amide), 2 (oxazole) and 3 (thiazole) and only proceed to designs 4, 5 and 6 if interesting activity is observed for designs 2 and/or 3.
Protein-ligand complexes were energy minimized with Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at their crystallographic positions) using the A chain of the P0157 crystal structure (ligand: PET-UNK-29afea89-2) in which the side chain amide of N142 has been rotated by 180 degree prior to energy minimization. The PDB file associated with the submission contains the following structures  Protein from energy minimized structure of complex with conformation 1 of design 2 (oxazole) [2-3] Binding modes predicted for PET-UNK-49566573-1 and PET-UNK-49566573-2 (these are homologs of Design 1 and CHO-MSK-5891c1ff-10 respectively and were included to show how insertion of methylene allows amide carbonyl to accept a hydrogen bond from the side chain amide of N142 side chain) [5-6] Two binding modes predicted for CHO-MSK-5891c1ff-10 [7-18] Binding modes predicted for Designs 1-6 (two per design).