Submission Details

Design Rationale:

The six designs combine two substituents (cyanomethyl; propargyl) on the cyclic sulfonamide nitrogen with three configuration lock variations (unlocked, methyl, methoxy). A substituent on the nitrogen of the cyclic sulfomamide is likely to adopt an axial orientation and this will make it difficult to engineer significant contact between substituent and protein. However, it is possible that contact between the N-substituent and the P1 isoquinoline may be beneficial (this appears to be the case for the tetrahydroisoquinoline MAT-POS-4223bc15-23) and the two N-substituents have been selected (unsaturated carbon without hydrolysis risk of amide) with this in mind. The racemates for the six designs have also been included in the submission.

Other Notes:

Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3] Binding mode predicted for MAT-POS-e119ab4f-5 [4-9] Binding modes predicted for Binding modes predicted for Designs 1-6.

Inspired By:

PET-UNK-1abb40f2-1

MAT-POS-c88128cb-3

ALP-POS-a577c8a2-1

ALP-POS-1cbc2fae-1

MAT-POS-c88128cb-6

MAT-POS-83f73d0a-3

MAT-POS-e119ab4f-5

ALP-POS-a577c8a2-2

MAT-POS-83f73d0a-4

PET-UNK-1abb40f2-2