Submission Details

Design Rationale:

The 4 designs in this submission submitted as single enantiomers replace the pendant secondary amides in EDJ-MED-015fb6b4-2 (IC50 = 56 nM) and EDJ-MED-015fb6b4-1 with acetylene or cyano (I have also included racemates for Designs 1-4 as racemates to give a total of 8 designs). While the pendant amide does not appear to form hydrogen bonds with the protein although there does appear to be some non-hydrogen bonded contact between the amide and the P1 isoquinoline in the crystal structure (P1090) for the complex with MAT-POS-4223bc15-23. My view is that the potency benefit resulting from the NH of the pendant amide of MAT-POS-4223bc15-23 is due to stabilization of the bound conformation. It is possible that non-covalent interactions between the pendant amide and P1-isoquinoline also stabilize the bound conformation (especially with respect to the orientation between the planes of the amide and isoquinoline substructures). The N-cyanomethyl tetrahydroisoquinoline PET-UNK-162c14b2-1 has been submitted and racemate MAT-POS-61f37a1a-12 (IC50 = 330 nM) has been assayed. Substituting the benzylic methylene of PET-UNK-162c14b2-1 with carbonyl (tetrahydroisoquinoline => dihydroisoquinolone) is likely to help the cyanomethyl group make contact with the P1 isoquinoline and also allow substituents like propargyl to be used since it is no longer necessary to suppress protonation of the tetrahydroisquinoline nitrogen. This submission is related to PET-UNK-37251634 and PET-UNK-f360ae44 submissions.

Other Notes:

Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen corresponding to the crystallographic ligand. The PDB file associated with this submission contains the following: [1] P0601 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [[3-6] Binding modes predicted for Designs 1-4.

Inspired By:

Download PDB File