Abstract:
The structure-based virtual screening (SBVS) has gained immense importance in early drug discovery. Herein, we report the SBVS-driven identification of new cholinesterase inhibitors from a library of FDA-approved small molecule drugs (n=1760). The in vitro validation of top SBVS hits provided azelastine, dronedarone, and iloperidone as acetylcholinesterase (AChE) inhibitors with IC50 values of 9.2, 18.2, and 23.0 μM, respectively. The in vitro screening of top actives in the butyrylcholinesterase (BChE) inhibition assay provided carvedilol as a potent BChE inhibitor with an IC50 of 0.8 μM. Azelastine also inhibits BChE with IC50 of 4.89 μM, indicating its dual ChE inhibition activity. Azelastine and carvedilol also inhibit the self-aggregation of Aβ1–42 with IC50 values of 4.6 and 2.2 μM, respectively. Both drugs cross blood-brain barrier (BBB), as indicated by the parallel artificial membrane permeation assay. Results presented herein warrant exploring the repurposing potential of azelastine and carvedilol for Alzheimer's disease.