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The article discusses the repurposing of USFDA-approved drugs to identify leads for the inhibition of the acetylcholinesterase enzyme as a potential anti-Alzheimer agent. Through Structure-Based Virtual Screening and in vitro assessments, domperidone was identified as a lead compound with inhibitory effects on AChE. However, due to its poor BBB permeability, new analogues were proposed using bioisosterism principles. These analogues showed improved properties and may be synthesized in the future for further exploration as new anti-Alzheimer agents.
In the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on the approved USFDA small molecules. Herein, we report the Structure-Based Virtual Screening (SBVS) of 1880 USFDA-approved drugs. The in silico-based identification was followed by calculating Prime MMGB-SA binding energy and molecular dynamic simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated via in vitro using anticholinesterase-based assessment, keeping donepezil positive control. The analysis revealed that the identified lead (domperidone) could induce an inhibitory effect on AChE in a dose-dependent manner with an IC50 of 3.67 µM as compared to the donepezil, which exhibited an IC50 of 1.37 µM. However, as domperidone is known to have poor BBB permeability, we rationally proposed new analogues utilizing the principles of bioisosterism. The bioisosteres-clubbed analogues were found to have better BBB permeability, affinity, and stability within the catalytic domain of AChE via molecular docking and dynamics studies. The proposed bioisosteres may be synthesized in the future. They may plausibly be explored for their implication in the developmental progress of new anti-Alzheimer agents achieved via repurposing techniques in future.
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