Molecular shape similarity of cyclic imides and protoporphyrinogen IX

N-Aryl-3,4,5,6-tetrahydrophthalimides, 4-aryl-1,2-tetramethylene-1,2,4-triazolidines, 5-aryl-3,4-tetramethylene-1,3,4-thiadiazolidines, 3-aryl-1,5-tetramethylenehydantoins and 3-aryl-5-isopropylidene-1,3-oxazolidine-2,4-dione are inhibitors of chlorophyll biosynthesis. The target enzyme is protoporphyrinogen IX oxidase (protox), and these inhibitors interact competitively with the substrate. To estimate a steric similarity between cyclic imides and protoporphyrinogen IX (protogen), the most stable molecular structure of these compounds was calculated and optimized by MOPAC with MNDO-PM3 parameterizations, and their steric properties were compared by computational techniques. For the most stable conformation of cyclic imides, the torsion angles between the imide moiety and benzene ring was approx. 240 degrees-270 degrees. By examining the superimposition patterns, cyclic imides were found to match with the C and D rings of protogen. The 2-carboxyethyl group at the C ring matched with the meta substituent on the benzene ring of the protox inhibitors. The value of the shape similarity index (S) were in the range of 0.62-0.85 when protogen and cyclic imides were superimposed by the least square fitting, using the most stable conformation of the protogen molecule. A good correlation was found between S and the protox inhibitory index. There is a similarity in the recognition of protox between inhibitors and substructural substrate.