Submission Details

Design Rationale:

The submission consists of 3 acetyl-tetrahydroisoquinolines (Design 2 is the S enantiomer of MAT-POS-dd3ad2b5-2 and this is indicated in the PDB file associated with the submission) and 12 analogs with oxadiazole as a non-hydrolyzable, amide replacement. The obvious first step to in using these non-hydrolyzable amide replacements would be to establish potency for the parent N-acetyl tetrahydroisoquinoline and I do not anticipate significant potency gains to result from replacing acetyl with oxadiazole. If using these non-hydrolyzable amide replacements, I would recommend synthesizing one or more of the 1,3,4-oxadiazoles (Designs 4-7) since these are likely to have better physicochemical characteristics than the corresponding 1,2,4-oxadiazoles (see Boström et al https://doi.org/10.1021%2Fjm2013248 | Goldberg et al https://doi.org/10.1039/C2MD20054F ). I have included the corresponding 1,2,4-oxadiazoles in the submission in case these are of interest to the design team.

Other Notes:

Protein-ligand complexes were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The P0157 A chain was used for modelling designs with methoxy on the tetrahydroisoquinoline and the X11612 A chain was used for modelling designs lacking this structural feature. The PDB file associated with this submission contains the following: [1] P0157 A chain [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3] X11612 A chain [4] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [5] Binding mode predicted for PET-UNK-9bf1291a-3 [6-20] Binding modes predicted for Designs 1-15

Inspired By:

BEN-DND-f2e727cd-5

MAT-POS-dd3ad2b5-2

PET-UNK-9bf1291a-3

MAT-POS-3ccb8ef6-1