These designs aim to present a heteroaromatic nitrogen to the side chain amide NH of N142 and can be regarded as analogous to sulfone PET-UNK-4880b143-1 and amides PET-UNK-49566573-1 and PET-UNK-49566573-2. I think that the basic idea could be tested with Design 1 (1,2,3-triazole) and although I’ve included three additional designs (pyridazine, 1,3,4-oxadiazole, 1,3,4-thiadazole) in case interesting activity is observed for design 1 (or if the designs are of interest to the design team). I would anticipate that potency gains relative to PET-UNK-29afea89-2 will be greater for PET-UNK-4880b143-1, PET-UNK-49566573-1, PET-UNK-49566573-2 than for any of the designs in the current submission. My recommendation would be to start by synthesizing Design 1, only proceeding with Designs 2, 3 or 4 if interesting activity is observed.
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 1 (1,2,3-triazole)  Crystallographic ligand: PET-UNK-29afea89-2) from P0157 A chain [3-5] Predicted binding modes for PET-UNK-4880b143-1, PET-UNK-49566573-1 and PET-UNK-49566573-2 [6-9] Predicted binding modes for designs 1-4.