Submission Details
Molecule(s):
CC(=O)NCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
CC(=O)N(C)CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
CS(=O)(=O)NCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
CN(CCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21)S(C)(=O)=O
N#CCCO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2ccc(Cl)cc21
Design Rationale:
The five designs in this submission are intended to make non-polar contact with the ‘floor’ of the S1 subsite while attempting to minimize contact between polar ligand atoms with non-polar molecular surface of the protein. Only the methylsulfonyl oxygen (Design 3 and Design 4) appears to accept hydrogen bonds from the protein and the amide oxygens in Design 1 and Design 2 are solvent exposed. The N-methyl analogs (Design 2 and Design 4) appear to better prospects than their des-methyl equivalents Design 1 and Design 3).
Other Notes:
Protein-ligand complexes were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The PDB file associated with this submission contains the following: [1] Protein from the energy-minimized complex with Design 4 [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-7] Designs 1-5.