Classical and Hologram QSAR Studies on a Series of Tacrine Derivatives as Butyrylcholinesterase Inhibitors

Alzheimer's disease (AD) is a major neurodegenerative disease that affects mainly people over 65 years of age. The main therapeutic approach to AD is based on the use of acetylcholinesterase (AChE) inhibitors. Recent studies have shown that butyrylcholinesterase (BuChE) can also be considered an attractive target for the development of novel drugs for AD therapy. The design of new potent and selective BuChE inhibitors is of great importance in drug discovery. 2D quantitative structure-activity relationship studies were conducted on a series of potent inhibitors of human BuChE using classical and hologram QSAR (HQSAR) approaches. A training set of 40 compounds was employed to derive the models. Classical QSAR models showed moderate correlation (r2 = 0.836, q2 = 0.750), with no substantial predictive power for untested compounds. On the other hand, the best HQSAR model (r2 = 0.928, q2 = 0.723) was used to predict the potency of 10 test set compounds, and the predicted values were in good agreement with the experimental results, showing the potential of this model for new untested compounds.