Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@]1(OCC2COC2)CCOc2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@]1(OCC2CS(=O)(=O)C2)CCOc2ccc(Cl)cc21
Design Rationale:
The two designs in this submission insert oxygen (Design 1) or sulfonyl (Design 2) into the cyclopropane ring of MIC-UNK-5d22d78d-1 in a manner that does not generate a chiral center. The binding mode predicted for each design shows unconvincing contact (~2.6 Å) with a hydrogen bond donor in the oxyanion hole region. Whether these interactions are real, the designs appear to be able to make non-polar contact with the hydrophobic ‘floor’ of the S1’ subsite without making destabilizing contacts with non-polar regions of the protein molecular surface.
Other Notes:
Protein-ligand complexes were energy minimized with Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at their crystallographic positions) using the A chain of the P0157 crystal structure (ligand: PET-UNK-29afea89-2) in which the side chain amide of N142 has been rotated by 180 degree prior to energy minimization. The PDB file associated with the submission contains the following structures [1] Protein from energy minimized structure of complex with conformation 1 of Design 1 (oxetane) [2] Crystallographic ligand: PET-UNK-29afea89-2) from P0157 A chain [3] Binding mode predicted for MIC-UNK-5d22d78d-1 [4-5] Binding modes predicted for Design 1 and Design 2.