Submission Details
Molecule(s):
N#C[C@H]1CO[C@@H](c2cccc(Cl)c2)C(=O)N1c1cncc2ccccc12
N#C[C@H]1C[C@@H](c2cccc(Cl)c2)C(=O)N1c1cncc2ccccc12
Design Rationale:
Each of the two designs in this submission is intended to present a nitrile warhead to the catalytic cysteine. I’ve built the models by simply editing the crystallographic ligands in the P0019 (PET-UNK-c9c1e0d8-3) and P0010 (PET-UNK-c9c1e0d8-4) crystal structures and the nitrile is built as an imine with carbon having an open valence. Design 1 is a less lipophilic analog of the previously submitted PET-UNK-3e354a91-1 and the configuration of the nitrile bearing carbon is likely to be more stable in the six-membered rings of this compound and Design 1 than in the five-membered ring of Design 2 (substituents on tetrahedral carbon next to cyclic amide nitrogen tend adopt axial orientation in absence of constraints). The warhead presentation in these designs is analogous to that in a number of gliptins (e.g. Saxagliptin) which feature a cyanopyrrolidine amide substructure.
Other Notes:
Models were generated by editing crystallographic ligands and energy minimization was not carried out. 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) [3-4] Predicted binding modes for PET-UNK-3e354a91-1 and Design 1 [5] P0010 A chain protein structure [6] P0010 A chain ligand (PET-UNK-c9c1e0d8-4) [7] Predicted binding mode for Design 2.