Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CNS(=O)(=O)c2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3ccccc23)CNS(=O)(=O)c2ccc(Cl)cc21
COC1(C(=O)Nc2cncc3ccccc23)CN(C)S(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The two designs in this submission add a methoxy configurational lock to the cyclic sulfonamides ALP-POS-a577c8a2-1 and ALP-POS-a577c8a2-2 (methoxy-locked chromane is about 3-fold more potent than methyl analog and alignment of C-O bond with amide NH may draw some of the latter’s sting). The instability of methoxy-locked dihydroisoquinolones is likely to be due to the planarity of the amide (the cyclic sulfonamide ring is geometrically more similar to a chromane). The racemate for each design has 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) [3-4] Binding modes predicted for ALP-POS-a577c8a2-1 and ALP-POS-a577c8a2-2 [5-6] Binding modes predicted for Designs 1 and 2.