Submission Details
Molecule(s):
O=C(Nc1cncc2sccc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1cncc2sccc12)[C@@H]1CCNc2ccc(Cl)cc21
O=C(Nc1cncc2sccc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sccc23)C1
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sccc23)C1
CC(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3sccc23)C1
O=C(Cc1cccc(Cl)c1)Nc1cncc2occc12
Design Rationale:
The designs in this submission are intended to address metabolic liability of the P1 isoquinoline. Designs 1-6 link the 6-azabenzothiophene P1 substituent of JIN-POS-6dc588a4-22 to different scaffolds (as discussed in the PET-UNK-0df12184 submission notes, I think that it would be a good idea to compare this heterocycle with isoquinoline from the perspective of metabolic stability). My recommendation to the design team would be to synthesize the design(s) corresponding to the scaffold(s) currently being used to assess isoquinoline replacements. I have also included Design 7 with 6-azabenzofuran at P1 (see MAR-UCB-fd2e172f-41) so that the substituent can be assessed for potency relative to isoquinoline in case this is of interest to the design team.
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 X11612 A chain was used for modelling. The PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3] Binding mode predicted for JIN-POS-6dc588a4-22 [4-10] Binding modes predicted for designs 1-7.