Submission Details
Molecule(s):
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@](F)(C(=O)Nc2cncc3ccccc23)C1
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@](F)(C(=O)Nc2cncc3ccccc23)C1
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)N2CC(C#N)C2)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)N2CC(C#N)C2)Cc2ccc(Cl)cc21
N#CC1CN(S(=O)(=O)N2Cc3ccc(Cl)cc3[C@](F)(C(=O)Nc3cncc4ccccc34)C2)C1
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@](F)(C(=O)Nc3cncc4ccccc34)C2)CC1
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@](F)(C(=O)Nc2cncc3cc(F)ccc23)C1
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@](F)(C(=O)Nc2cncc3cc(F)ccc23)C1
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(=O)(=O)N2CC(C#N)C2)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(=O)(=O)N2CC(C#N)C2)Cc2ccc(Cl)cc21
N#CC1CN(S(=O)(=O)N2Cc3ccc(Cl)cc3[C@](F)(C(=O)Nc3cncc4cc(F)ccc34)C2)C1
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@](F)(C(=O)Nc3cncc4cc(F)ccc34)C2)CC1
Design Rationale:
The designs in this submission (related to the PET-UNK-407a74a5 submission) replace the methoxy configurational lock with acetylenyl or fluoro for two sulfonamides (MAT-POS-24589f88-3; MAT-POS-dc2604c4-1) and two sulfamides (MAT-POS-4223bc15-2; EDJ-MED-1981ceba-4) derived from the tetrahydroisoquinoline scaffold. The methoxy-locked analogs of MAT-POS-dc2604c4-1 and EDJ-MED-1981ceba-4 have also been included since these do not appear to have been registered. Acetylenyl and fluoro 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) [3-22] Binding modes predicted for designs 1-20