Repurposing of FDA-Approved Drugs as Acetylcholinesterase Inhibitors for Alzheimer's Disease: A Combined In Silico and In Vitro Evaluation and Structure-Activity Relationship

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and decreased cholinergic activity that affects millions of individuals worldwide. Herein, in vitro acetylcholinesterase (AChE) inhibitory potentials of FDA-approved drugs identified by computational approaches, including structure-based virtual screening, molecular dynamics (MD) simulations, and molecular mechanics-generalized Born surface area (MM/GBSA), were carried out. The top docking poses of the selected drugs (Trazodone, Frovatriptan, Eletriptan, Bupropion, Rivaroxaban, Sotalol, and Indapamide) were analyzed during 200 ns MD simulations. The average root-mean-square deviation (RMSD) values along with standard deviation were calculated for all complexes between approximately 1.90 +/- 0.37 and 1.59 +/- 0.21 & Aring;. The average RMSD values of AChE-Trazodone and AChE-Rivaroxaban, respectively, were found to be 1.69 +/- 0.19 and 1.74 +/- 0.30 & Aring;. On the basis of in vitro findings, Trazodone (12.61 +/- 0.52 nM) showed 2.11-fold more inhibitory activity than donepezil (DNP). In vitro AChE activity of Rivaroxaban (26.82 +/- 0.51 nM) was found to be similar to DNP (26.67 +/- 0.56 nM). Frovatriptan, Eletriptan, Bupropion, Sotalol, and Indapamide had 1.84-, 1.70-, 1.67-, 1.29-, and 1.23-fold higher activity than tacrine. This study highlights the potency of the studied FDA-approved drugs to inhibit AChE for the treatment of AD through in silico and in vitro studies.