Submission Details
Molecule(s):
CC(C)(C#N)CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
O=C(Nc1cncc2ccccc12)[C@@H]1CN(S(=O)(=O)CN2CCC2)Cc2ccc(Cl)cc21
CN(C)CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
COCS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
Design Rationale:
The 4 designs in this submission are derived from MAT-POS-dc2604c4-1 and MAT-POS-4223bc15-12 each of which is about 4-fold more potent than MAT-POS-dd3ad2b5-4. While I’ve not been able to use the Mpro-P1007 crystal structure to generate plausible binding modes for MAT-POS-dc2604c4-1 or MAT-POS-4223bc15-12, I would consider Design 1 as an obvious target for synthesis with which to follow up the activity of these two inhibitors. If, as I suspect, the nitrile groups of MAT-POS-dc2604c4-1 and MAT-POS-4223bc15-12 are directed toward solvent then Design 2 would be an appropriate target for synthesis (lower molecular weight and less lipophilic with the sulfonyl group preventing significant ionization of the tertiary amine). Design 3 is the tertiary amine analog of Design 1 and I’ve also included the methoxy as Design 4.
Other Notes:
I have not (yet) been able to generate plausible binding modes for MAT-POS-dc2604c4-1 or MAT-POS-4223bc15-12 so there is no PDB file associated with this submission.