Three‐Dimensional Quantitative Structure‐Activity Relationship of Arylalkylamine N‐acetyltransferase (AANAT) Inhibitors: A Comparative Molecular Field Analysis

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to a series of 40 compounds synthesized in our laboratory and evaluated as AANAT inhibitors. The N-bromoacetyltryptamine conformation derived from the X-ray crystal structure of the enzyme bound with a bisubstrate analog, was used to obtain the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (30 compounds) and subsequently validated with the corresponding test sets (10 compounds). The best predictive model (n=30, q2=0.644, N=6, r2=0.966, s=0.145, F=109.478) can predict inhibitory activity for a wide range of compounds and offers important structural insight into designing novel AANAT inhibitors prior to their synthesis.