Submission Details
Molecule(s):
N#C[C@H]1CN[C@@H](c2cccc(Cl)c2)C(=O)N1c1cncc2ccccc12
CN1C[C@H](C#N)N(c2cncc3ccccc23)C(=O)[C@@H]1c1cccc(Cl)c1
Design Rationale:
Each of the two designs in this submission is intended to present a nitrile warhead to the catalytic cysteine. I’ve constructed the models by editing the crystallographic ligand in the P0019 (PET-UNK-c9c1e0d8-3) crystal structure, building the nitrile is built as an imine with open valence on carbon. Substituents on tetrahedral carbon next to cyclic amide nitrogen tend to adopt axial orientation in absence of constraints and this will stabilize the configuration of the nitrile-bearing carbon. I would anticipate that the more basic nitrogen in the piperazone will be predominantly neutral at physiological pH. D is a less lipophilic analog of the previously submitted PET-UNK-3e354a91-1. The warhead presentation in these designs is analogous to that in a number of gliptins (e.g. Saxagliptin) which feature a cyanopyrrolidine amide substructure. See also notes for PET-UNK-5ddd54c7 submission.
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 Designs 1-2.