Molecular Modeling Studies of Some Choline Acetyltransferase Inhibitors

Abstract

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 geometries 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 ring is twisted out of the plane by approximately 30 degrees. Where steric features significantly deter assumption of a nearly planar conformation, the analogs are inactive. The inactivity of analogs bearing tricyclic aryl groups appears to result from bulk-related hindrance to ChAT receptor binding rather than lack of coplanarity.

Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

“…An essentially coplanar conformation of the trans a-b-c region is believed to be important, although it does not cost much energy to adopt twisted conformations. The feasibility of the co-planarity hypothesis has been supported in an earlier computational chemistry study [10]. Optimum molecular features governing inhibitory potency include region a as a bicyclic aryl group or as a phenyl moiety with p-electron donor enhancing substituents, region b as a site of unsaturation typically with a double bond (a triple bond, although not used in this study, is also seen) and region c as a pyridinium or quinolinium system.…”

“…While most of the other less active compounds either partially touch the yellow contour or occupy unfavorable white region. With regards to a, earlier studies have proposed that substituents enhancing p-donor qualities are favorable for activity [10] This is clearly seen from the H-bond donor contours (cyan, favored; orange, disfavored) where the aryl group in the region a is close to the cyan contour which is favored for activity. The extended naphthyl group at a increases the p-donor abilities which could assist in hydrogen bonding to a nearby histidine residue [25].…”

“…Several of these variables have been identified or proposed for the a-b-c-d components of the molecule and for the molecule as a whole [10]. Component b which is a trans-vinyl linkage and component d which primarily serves to quaternize the N atom, do not appear to be structurally specific [23].…”

“…Analogs of trans-1-methyl-4-(1-naphthylvinyl)pyridinium (MNVP + ) ( Fig. 1) [6][7][8][9][10][11][12] are the simplest and most potent prototype. There are a few known features of MNVP + which appear essential for ChAT inhibition.…”

Synthesis of new vinylpyridinium salts

“…DeBernardis et al . established four structural moieties for the structure shown in Figure 2 as potentially responsible for strong inhibitory activity: (a) a mono or bicyclic aromatic system, [10]; (b) a double bond; (c) a pyridinium or quinolinium moiety; and (d) an alkylic chain. Other PSs, however, have shown low CAT inhibition activity [11].…”