Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@]1(OC(F)F)CCOc2ccc(Cl)cc21
Design Rationale:
This design is based (potential for electrostatic interaction) on the observation that one of the (modelled) methoxy hydrogen atoms of the PET-UNK-29afea89-2 crystallographic ligand is 3.1 Å from the H164 backbone amide carbonyl oxygen (this hydrogen bond acceptor appears relatively buried although the crystal structure points to an electrostatic interaction with one of the CHs of the P2 aryl ring). While difluorination of PET-UNK-29afea89-2 would be expected to favor the electrostatic interaction (and address metabolic issues associated with the methoxy), this structural modification will cut off access to the S1’ subsite and any necessary potency increases will need to be generated elsewhere.
Other Notes:
The model for the ligand has been generated by editing the crystallographic ligand PET-UNK-29afea89-2 and has not been energy-minimized. The PDB file associated with this submission contains the following: [1] P0157 A chain protein [2] Crystallographic ligand: PET-UNK-29afea89-2 from P0157 A chain [3] Binding mode predicted for Design 1