Molecular modeling studies of some choline acetyltransferase inhibitors

Choline acetyltransferase (ChAT) inhibitors related to trans-1-methyl-4-(1-naphthylvinyl)pyridinium (NVP + ) have been assumed to depend upon a nearly or completely planar conformation for their enzyme-inhibitor interaction. In an effort to investigate the geometies and preferred conformations for these compounds, geometry optimizations using the semiempirical molecular orbital method AM1 and a modified version of the molecular mechanics method MM2(92) have been carried out. The results indicate that the active inhibitors are either planar or nearly coplanar, lying in relatively flat potential wells in the vicinity of the corresponding planar structures. When nonplanarity is favored, one ing is twisted out of the plane by approximately 30 o