Loading...
Repurposing of USFDA-approved drugs to identify leads for inhibition of acetylcholinesterase enzyme: a plausible utility as an anti-Alzheimer agent
Goel, K.K. Chahal, S. Kumar, D. Jaiswal, S. Nainwal, N. Singh, R. Mahajan, S. Rawat, P. Yadav, S. Fartyal, P.
Goel, K.K.
Chahal, S.
Kumar, D.
Jaiswal, S.
Nainwal, N.
Singh, R.
Mahajan, S.
Rawat, P.
Yadav, S.
Fartyal, P.
Publication Date
2024-09-16
End of Embargo
Supervisor
Rights
Peer-Reviewed
Yes
Open Access status
restrictedAccess
Accepted for publication
2024-09-10
Institution
Department
Awarded
Embargo end date
Collections
Additional title
Abstract
In the quest to identify new anti-Alzheimer agents, we employed drug repositioning or drug repositioning techniques on 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 dynamics simulation studies. The cumulative analysis led to identifying domperidone as an identified hit. Domperidone was further corroborated in vitro using anticholinesterase-based assessment, keeping donepezil as a 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 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 bioisostere-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 agent achieved via repurposing techniques in future.
Version
No full-text in the repository
Citation
Goel KK, Chahal S, Kumar D, et al (2024) Repurposing of USFDA-approved drugs to identify leads for inhibition of acetylcholinesterase enzyme: a plausible utility as an anti-Alzheimer agent. RSC Medicinal Chemistry 15: 4138-4152.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article