Submission Details
Molecule(s):
CCc1cc(Cl)cc(CC(=O)Nc2cncc3ccccc23)c1
O=C(Cc1cc(Cl)cc(OC(F)(F)F)c1)Nc1cncc2ccccc12
CCCc1cc(Cl)cc(CC(=O)Nc2cncc3ccccc23)c1
Design Rationale:
Evaluate smaller and more flexible P4 substituents that can potentially exploit the S4 subsite without completely blocking access of solvent to the backbone carbonyl of E166. The CF3O substituent of the design 2 tends (analysis of CSD) to be twisted out of coplanarity with the benzene ring and is sufficiently electron-withdrawing to protect the benzene ring from CYP-catalyzed oxidation.
Other Notes:
The PDB file contains (1) Protein structure from x10789 (2) TRY-UNI-2eddb1ff-7 ligand from x10789 (3) Fragment AAR-POS-d2a4d1df-2 from x0104 (4) Designs 1-4 from PET-UNK-b87f07d0 submission (5) Designs 1-2 from PET-UNK-c5865d42 submission (6) Designs 1-3 from current submission. Binding modes for previous and current designs given in pdb file have been energy-minimized (MMFF94S) in with szybki (OpenEye). The binding modes for previous designs in this pdb file are revisions of the binding modes originally presented with those designs.