In silico exploration of promising heterocyclic molecules against both acetylcholinesterase and butyrylcholinesterase enzymes

We aimed to further explore the relationship between heterocyclic molecules and their associated biological activities for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A dataset of 36 heterocycles was used to predict the activity of AChE and BChE inhibitors (the pIC50 values ranged from 7.84 to 12.49). A quantitative structure-activity relationship (QSAR) study was generated with the help of four different models (BMA, MNLR, MLR, and ANN). Four of the models were statistically acceptable based on both internal and external validation. The descriptors used in the models were similar to the X-ray structures of the target-ligand complexes, which made it possible to predict the pIC50 for AChE and BChE enzymes. Five selected molecules (compounds 6 (C21H21F3N4O), compound 7 (C22H23F3N4O), and compound 8 (C22H23F3N4O2) belong to the oxadiazole derivative group; compound 16 (C17H13ClN2O3) is classified into the chemical structures of different N, O, and S-based heterocycle groups; and compound 25 (C19H17NO2) pertains to the pyrimidine derivative group) possessed high pIC50 values for AChE and BChE enzymes (pIC50 values for AChE and BChE ranged from 9.01 to 10.32). The range of docking scores between the AChE and BChE receptors and their respective candidates was from −8.1 to −9.2 kcal/mol. The pharmacokinetics, biological activities, and physicochemical properties of five selected compounds supported their ability to protect against AD because they are not toxic, have a cholinergic effect, can cross the blood-brain barrier, and are well absorbed by the gastrointestinal tract.Communicated by Ramaswamy H. Sarma