Submission Details
Molecule(s):
COC(=O)CN1C[C@@H](C(=O)Nc2cncc3ccccc23)c2cc(Cl)ccc2C1=O
COC(=O)CN1CC(C(=O)Nc2cncc3ccccc23)c2cc(Cl)ccc2C1=O
Design Rationale:
The single design (submitted both as a single enantiomer and racemate) in this submission replaces the pendant N-methylamide of the dihydroisquinolone EDJ-MED-015fb6b4-2 (IC50 = 56 nM) with a methyl ester and has been submitted as an easily synthesized analog to assess the importance of pendant amide NH as a determinant of potency. The case for the oxadiazoles (more ester mimic than amide mimic) such as PET-UNK-37251634-3 would be strengthened if replacement of the pendant amide NH with O proved to be well tolerated. The crystal structure of the MPro complex with the tetrahydroisoquinoline MAT-POS-4223bc15-23 indicates that the pendant amide NH does not make contact with the protein and its role appears to be to stabilize the bound conformation. There are potential interactions between the pendant amide NH and both the tetrahydroisoquinolone nitrogen and the carbonyl oxygen of the central amide.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P0601 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3] Binding mode predicted for Design 1