Submission Details

Design Rationale:

Each of the three designs in this submission replaces the pendant amide of MAT-POS-4223bc15-23 with 1,3,4-thiadiazole for three spirocyclic fusions (pyrrolidinone, piperidinone, morpholinone) with the dihydroisoquinolone scaffold. The pendant group has been designed to use an interaction (the term ‘chalcogen bonding’ is sometimes used to describe interactions like these) between sulfur and the tetrahydroisoquinoline lone pair to stabilize a conformation that mimics that of the pendant amide of MAT-POS-4223bc15-23. I’ll add a comment to this submission with a graphic illustrating the alignment and links to structures in the CSD (not feasible to do so in submission notes). The three designs have also been submitted as racemates.

Other Notes:

Protein-ligand complexes (P1090 A chain) were first energy-minimized using Szybki (MMFF94S). In each case, the pendant group was then manually aligned with the pendant amide of the P1090 A chain crystallographic ligand (MMFF94 does not appear to handle the interaction between S and the THIQ lone pair suggested by the KAGFEG CSD structure). The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-5] Binding modes predicted for Designs 1-3

Inspired By:

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