Submission Details
Molecule(s):
CC(C)C[C@H](NC(=O)NCc1ccccc1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)C(=O)C(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
CC(C)C[C@H](NC(=O)NCc1ccccc1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)C(=O)C(=O)Nc1cc(O)c(F)cc1F
COc1cccc(NC(=O)C(=O)[C@H](C[C@@H]2CCNC2=O)NC(=O)[C@H](CC(C)C)NC(=O)Nc2c(F)ccc(O)c2F)c1
COc1cc(NC(=O)C(=O)[C@H](C[C@@H]2CCNC2=O)NC(=O)[C@H](CC(C)C)NC(=O)N(Cc2ccccc2)C2CCCCO2)cc(OC)c1
CC(C)C[C@H](NS(=O)(=O)NCc1ccccc1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)C(=O)C(=O)Nc1cc(O)c(F)cc1F
COc1cc(F)cc(NC(=O)C(=O)[C@H](C[C@@H]2CCNC2=O)NC(=O)[C@H](CC(C)C)NC(=O)NCc2ccccc2)c1
Design Rationale:
These compounds are inspired by the alpha-ketoamide bound crystal structure (6Y2F) and designed based on our experience on the lead-optimization of alpha-ketoamides for inhibiting a cysteine protease calpain2 (J Am Chem Soc. 2017,doi.org/10.1021/jacs.7b08938). To achieve the optimal binding, we kept the P1 and P2 sidechains to mimic the substrate peptide, and explored the chemical space of P1' and P3 using the fragment map-based approach described in J. Chem. Inf. Model. 2019, doi.org/10.1021/acs.jcim.8b00959. The fragment maps were obtained from http://demo.silcsbio.com/covid-19/.