Submission Details
Molecule(s):
O=C1C(c2cncc3ccccc23)=CCN1c1cccc(Cl)c1
O=C1C(c2cncc3ccccc23)=CCCN1c1cccc(Cl)c1
Design Rationale:
The two designs in this speculative submission hybridize the acrylamide BEN-DND-031a96cc-8 (inactive in enzyme inhibition assay; crystal structure indicates that covalent bond does not form) with each of the lactams PET-UNK-c9c1e0d8-3 and PET-UNK-c9c1e0d8-4. Annulation of the acrylamide may improve warhead access to the catalytic cysteine and the P1 4-isoquinolinyl and P2 chlorophenyl could stabilize transition state to greater extent than P1 3-pyridine and P2 phenyl equivalents in BEN-DND-031a96cc-8. I would recommend synthesizing PET-UNK-5ecb6237-1 (likely to be readily accessible from the parent amide by reaction with cyanogen bromide) before attempting synthesis of either design.
Other Notes:
Protein-ligand complexes (P0019 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0019 A chain protein structure [2] P1090 A chain crystallographic ligand (PET-UNK-c9c1e0d8-3) [3-4] Binding modes predicted Designs 1 and 2.