Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@@H]1CN(S(=O)(=O)N2CCCC2)Cc2ccc(Cl)cc21
CC(C)(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
CC(C)(C#N)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
O=C(Nc1cncc2ccccc12)[C@@H]1CN(S(=O)(=O)N2CCC(F)(F)C2)Cc2ccc(Cl)cc21
Design Rationale:
The four tetahydroisoquinoline designs in this submission consist of two sulfamides and two sulfonamides. Design 1 is the des-methyl analog of MAT-POS-4223bc15-11 (modelling suggests that the methyl group can be eliminated and this would remove both a chiral center and a potentially vulnerable tertiary alkyl center). Design 2 replaces the NMe2 group of MAT-POS-4223bc15-2 with t-butyl (two of the t-butyl methyls match the NMe2 methyls while the third methyl appears to make some contact with the protein). Design 3 replaces one the t-butyl methyls of Design 2 with nitrile which is directed toward the oxyanion hole region (in the model there is an unconvincing hydrogen bond between the nitrile and the side chain amide NH of N142). Design 4 aims to harden Design 1 with respect to metabolism (I see this design as a lower priority than the first three designs at this stage).
Other Notes:
Protein-ligand complexes (X11612 A chain) were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The PDB file associated with this submission contains the following: [1] X11612 A chain from complex with Design 3 [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-5] Binding modes predicted for MAT-POS-4223bc15-12 | MAT-POS-4223bc15-11 | EDJ-MED-1981ceba-2 [6-9] Binding modes predicted for designs 1-4