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.
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  Protein from energy minimized structure of complex with conformation 1 of Design 1 (oxetane)  Crystallographic ligand: PET-UNK-29afea89-2) from P0157 A chain  Binding mode predicted for MIC-UNK-5d22d78d-1 [4-5] Binding modes predicted for Design 1 and Design 2.