Submission Details
Molecule(s):
COCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
COCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
COCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CNC(=O)c2ccc(Cl)cc21
COCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(C)C(=O)c2ccc(Cl)cc21
COCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCS(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The designs in this submission elaborate the methoxy substituent (configurational lock which also appears to be beneficial for antiviral activity). A single P1’ substituent is used (as discussed with Ed Griffen, synthesis would be a carried out by first reacting the hydroxy starting material with ethylene oxide) and this is combined with different scaffolds of potential interest to design team.
Other Notes:
Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S). As modelled the methoxy oxygen accepts a hydrogen bond from N142 although this is not entirely convincing and the methoxy oxygen might also be solvent exposed. The PDB file associated with this submission contains the following: [1] P0157 A chain from complex with design 1 [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-7] Binding mode predicted for designs 1-5.