Discovery of Novel Acetylcholinesterase Inhibitors by Virtual Screening, In Vitro Screening, and Molecular Dynamics Simulations

Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomicproblem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors ofacetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potentialinhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble ofbinding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submittedfor in vitro screening, which led to 25 hits being identified with IC50values of less than 50 mu M. The majority of these hits belongedto two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to bepromising compounds for further optimization. As various possible binding poses were suggested from molecular docking, moleculardynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stablewater bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets ofcompounds that are not able to form this water bridge.