Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@@H]1CN(Cc2nncs2)Cc2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@@H]1CN(Cc2ncns2)Cc2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@@H]1CN(Cc2nccs2)Cc2ccc(Cl)cc21
Design Rationale:
The 3 designs (2 x thiadiazole isomers; 1 x thiazole) in the submission are derived from MAT-POS-4223bc15-23 and EDJ-MED-fa7708b3-2. The basis for the submission is the ability of sulfur to mimic an NH hydrogen bond (chalcogen bonding). Observed SAR (MAT-POS-4223bc15-25 MAT-POS-4223bc15-23 > MAT-POS-4223bc15-24) suggests that, when bound, the amide NH eclipses the lone pair of the tetrahydroisoquinoline nitrogen (neutral because of inductive effect of amide carbonyl) and this would be consistent with what is observed in small molecule crystal structures. EDJ-MED-fa7708b3-2 would be expected to adopt an analogous conformation and thiadiazole sulfur may be able to mimic the azole NH. The thiazole sulfur appears to be able to get within striking distance of the backbone amide carbonyl oxygen of E166 (a molecular recognition element used by a number of inhibitors). I would recommend synthesis of Design 1 (1,3,4-thiadiazole) in the first instance since it it is likely to be more polar than Design 2 (1,2,4-thiadiazole) and the aza-nitrogens are more solvent exposed. The thiadiazole sulfurs of Designs 1 and 2 are likely (electronegativity) to be better chalocogen donors than the thiazole sulfur of Design 3 and the thiadiazoles are more strongly electron withdrawing (better able to maintain neutrality of tetrahhydroisoquinoline) than thiazole.
Other Notes:
Protein-ligand complexes (P0157 A chain from complex with Design 1) were energy-minimized using Szybki (MMFF94S). The relevant NH or S was positioned to eclipse the tetrahydroisoquinoline nitrogen at the start of each energy minimization during which its coordinates were fixed. Two poses were generated for each ligand (in each case, pose 1 inherits the pucker of a chromane lacking a configuration lock such as methoxy and is the more probable binding mode). The PDB file associated with this submission contains the following: [1] P0157 A chain [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-4] Binding modes predicted for MAT-POS-4223bc15-23 [5-6] Binding modes predicted for EDJ-MED-fa7708b3-2 [7-12] Binding modes predicted for Designs 1-3.