Submission Details
Molecule(s):
CN(C)C(=O)CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
O=C(CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21)N1CCC1
CN(C)C(=O)CCO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CCOc2ccc(Cl)cc21
O=C(CCO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CCOc2ccc(Cl)cc21)N1CCC1
Design Rationale:
These designs (tertiary amides) are closely related to the PET-UNK-4880b143-1 design (a sulfone) and they are intended to make non-polar contact with the S1' region while presenting polarity to solvent (or HB donors of oxyanion hole).
Other Notes:
Designs 1/2 have also been submitted as their 6-fluoro (isoquinoline) analogs (designs 3/4). The A-chain of P0157 (ligand: PET-UNK-29afea89-2) was used to generate binding modes (MMFF94S using syzbki; isoquinoline N and secondary amide O constrained according to crystallographic ligand). The pdb file associated with the submission contains (1) Protein structure from energy-minimized complex with design 1 (2) Crystallographic ligand (PET-UNK-29afea89-2) (3) Binding mode generated previously for PET-UNK-4880b143-1 (4) The four designs (not in submission order). I would not expect the the hydrogen bond between the tertiary amide O and the N142 side chain NH2 to contribute significantly to affinity and may be an artifact (if this is the case, the tertiary amide O should still be exposed to solvent).