Submission Details

Design Rationale:

The four designs in this submission are derived from the designs of the EDJ-MED-fed7ac0b submission which are intended to donate a hydrogen bond to the catalytic cysteine thiol. The NH hydrogen bond donor in question is likely to be directed away from the catalytic cysteine thiol for the designs in the EDJ-MED-fed7ac0b submission (5-membered ring). For the analogous 6-membered ring is likely to be directed at the catalytic cysteine thiol although my assessment is that the hydrogen bond, even it forms, would be unlikely to contribute significantly to affinity. I see the real value of these ring systems as providing a synthetic handle for accessing the catalytic cysteine and/or the oxyanion hole. The designs are (1) 6-membered ring (2) 5-membered ring (3) N-cyano analog of 6-membered ring (targets catalytic cysteine) (4) N-cyano analog of 5-membered ring (targets oxyanion hole). The designs are non-spirocyclic (presumably more easily synthesized) analogs of the designs in the EDJ-MED-fed7ac0b submission and I see the 6-membered rings (Designs 1 and 3) as of greatest interest. The racemates for the designs have been included in this submission.

Other Notes:

Protein-ligand complexes (P0019 A chain from which catalytic cysteine thiol had been deleted) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0019 A chain protein structure [2] P0019 A chain ligand (PET-UNK-c9c1e0d8-3) [3-6] Predicted non-covalent binding modes for Designs 1-4.

Inspired By:

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