In silico identification of novel heterocyclic compounds combats Alzheimer's disease through inhibition of butyrylcholinesterase enzymatic activity

Increasing evidence indicates that heterocyclic molecules possess properties against butyrylcholinesterase (BChE) enzymatic activity, which is a potential therapeutic target for Alzheimer's disease (AD). Thus, this study aimed to further evaluate the relationship between heterocyclic molecules and their biological activities. A dataset of 38 selective and potent heterocyclic compounds (-log[the half-maximal inhibitory concentration (pIC50)]) values ranging from 8.02 to 10.05) was applied to construct a quantitative structure-activity relationship (QSAR) study, including Bayesian model average (BMA), artificial neural network (ANN), multiple nonlinear regression (MNLR), and multiple linear regression (MLR) models. Four models met statistical acceptance in internal and external validation. The ANN model was superior to other models in predicting the pIC50 of the outcome. The descriptors put into the models were found to be comparable with the target-ligand complex X-ray structures, making these models interpretable. Three selected molecules possess drug-like properties (pIC50 values ranged from 9.19 to 9.54). The docking score between candidates and the BChE receptor (RCSB ID 6EYF) ranged from -8.4 to -9.0 kcal/mol. Remarkably, the pharmacokinetics, biological activities, molecular dynamics, and physicochemical properties of compound 18 (C20H22N4O, pIC50 value = 9.33, oxadiazole derivative group) support its protective effects on AD treatment due to its non-toxic nature, non-carcinogen, cholinergic nature, capability to penetrate the blood-brain barrier, and high gastrointestinal absorption. [GRAPHICS]