Submission Details
Molecule(s):
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CCS(=O)(=O)c2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CS(=O)(=O)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CNC(=O)c2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(C)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@]1(F)CCOc2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@]1(F)CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@]1(F)CS(=O)(=O)Cc2ccc(Cl)cc21
O=C1NC[C@@](F)(C(=O)Nc2cncc3ccccc23)c2cc(Cl)ccc21
CN1C[C@@](F)(C(=O)Nc2cncc3cc(F)ccc23)c2cc(Cl)ccc2C1=O
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CCOc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CCS(=O)(=O)c2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CS(=O)(=O)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CNC(=O)c2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(C)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)ccc12)[C@]1(F)CCOc2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)ccc12)[C@]1(F)CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)ccc12)[C@]1(F)CS(=O)(=O)Cc2ccc(Cl)cc21
O=C1NC[C@@](F)(C(=O)Nc2cncc3cc(F)ccc23)c2cc(Cl)ccc21
Design Rationale:
The designs in this submission replace the methoxy configurational lock with acetylenyl or fluoro for a number of scaffolds of interest. These two substituents can potentially align with the amide NH which may be beneficial for translation of enzyme inhibition to antiviral activity in the cell-based assay (as I understand is the case for methoxy). I would recommend using the acetylenyl substituent as an alternative to methyl/alkyl if elimination of methanol from methoxy-locked inhibitors is an issue and also to provide access to the S1’ region (see PET-UNK-29afea89 design notes). I have also included fluoro-locked analogs just in case these are of interest to the design team (e.g. to address metabolism of the methoxy configurational lock). I would anticipate that these will be less potent than the corresponding methoxy analogs and the fluoro substitution will cut off access to the S1’ region. I have also submitted the corresponding 7-fluoroisoquinolines in the light of the improved metabolic stability of EDJ-MED-b7309adf-1 (see also PET-UNK-03fd2068 design notes).
Other Notes:
Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0157 A chain protein structure [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3] Binding mode predicted for PET-UNK-29afea89-1 [3-21] Designs 1-19.