Submission Details
Molecule(s):
CS(=O)(=O)Nc1ccc2c(c1)c(=O)n(-c1cncc(N)c1)c(=O)n2-c1ncc[nH]1
Design Rationale:
The submitted compound was tested using 0.2 micro-second Gaussian accelerated Molecular Dynamics simulation in AMBER software. The compound was highly stable and makes several consistent interactions with the binding site residues throughout the simulation, such as: 1. The pyridine N makes a very strong hydrogen bond with nearby His163 sidechain. 2. The same pyridine creates an aromatic interaction environment with nearby aromatic residues, His163 and His172. 3. The terminal amino group on pyridine ring, on the virtue of being protonated at physiological pH, makes a salt-bridge interaction with negatively-charged Glu166. 4. The same terminal amino group on pyridine ring, also makes a hydrogen bond with side-chain amide group of Asn142. 5. One of the carbonyl oxygens on the middle dipyrimidone-like ring makes the pivotal hydrogen bond interaction with backbone of His164. 6. The other carbonyl oxygen on the dipyrimidone-like ring could make a very likely interaction with backbone of Gly149, as this is present on a very long and flexible loop. The primary reason of making the dipyrimidone was to constrain the orientation of the molecule and connect different pieces of molecule. 7. The fused phenyl group of dipyrimidone-like entity provides critical aromatic interaction with aromatic residue His41. 8. The imidazole also makes a highly favorable aromatic interaction with side-chain of His41, along with a hydrogen bond between imidazole NH and N of His41. 9. The N-sulphonamide =O makes a hydrogen bond with backbone of Thr26, along with several hydrogen bonds with a network of waters. Please see notes for additional details.
Other Notes:
The initial design was inspired by visually identifying key pharmacophores of crystallized non-covalent fragments. After making the assessment that His41 and His163 provide consistent aromatic interactions in most fragments along with a hydrogen bond with backbone CO of His164, bound fragments Mpro-x0434_bound and Mpro-x0072_bound were selected for the initial idea. The submitted design was arrived at by analyzing nearby residues and attempting different aromatic ring substitution and different functional groups that had the right geometry for optimal interactions as well as drug-like properties.