Submission Details
Molecule(s):
CNC(=O)CN1C[C@@H](C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2C1=O
NC(=O)CN1C[C@@H](C(=O)Nc2cncc3ccccc23)c2cc(Cl)ccc2C1=O
N#CNC(=O)CN1C[C@@H](C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2C1=O
CNC(=O)CN1CC(C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2C1=O
NC(=O)CN1CC(C(=O)Nc2cncc3ccccc23)c2cc(Cl)ccc2C1=O
N#CNC(=O)CN1CC(C(=O)N(C#N)c2cncc3ccccc23)c2cc(Cl)ccc2C1=O
Design Rationale:
The three designs in this submission are intended to address amide hydrolysis as a clearance route for MAT-POS-a54ce14d-2. Design 1 places a cyano substituent on the nitrogen of the central amide (this can potentially form a covalent bond with the catalytic cysteine and may also result in a potency gain). Design 2 removes N-methyl of the pendant amide (for an enzymatic process it is possible that the primary amide might be an inferior substrate to the secondary amide). Design 3 places a cyano substituent on each amide nitrogen (Design 3 might be more easily synthesized than Design 1 if Design 2 is synthesized). The three designs have also been submitted as racemates.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the central amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3] Binding mode predicted for MAT-POS-a54ce14d-2 [4-6] Binding modes predicted for Designs 1-3.