Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease
Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholines...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Informatics in Medicine Unlocked |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352914823002265 |
| _version_ | 1797401766345572352 |
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| author | Ishtiaque Ahammad Zeshan Mahmud Chowdhury Arittra Bhattacharjee Sheikh Sunzid Ahmed Farzana Akter Mohammad Uzzal Hossain Keshob Chandra Das Chaman Ara Keya Md. Salimullah |
| author_facet | Ishtiaque Ahammad Zeshan Mahmud Chowdhury Arittra Bhattacharjee Sheikh Sunzid Ahmed Farzana Akter Mohammad Uzzal Hossain Keshob Chandra Das Chaman Ara Keya Md. Salimullah |
| author_sort | Ishtiaque Ahammad |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies. |
| first_indexed | 2024-03-09T02:14:52Z |
| format | Article |
| id | doaj.art-93eac49074064667b39e654c65d0c959 |
| institution | Directory Open Access Journal |
| issn | 2352-9148 |
| language | English |
| last_indexed | 2024-03-09T02:14:52Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Informatics in Medicine Unlocked |
| spelling | doaj.art-93eac49074064667b39e654c65d0c9592023-12-07T05:29:11ZengElsevierInformatics in Medicine Unlocked2352-91482023-01-0143101380Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's diseaseIshtiaque Ahammad0Zeshan Mahmud Chowdhury1Arittra Bhattacharjee2Sheikh Sunzid Ahmed3Farzana Akter4Mohammad Uzzal Hossain5Keshob Chandra Das6Chaman Ara Keya7Md. Salimullah8Bioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, BangladeshBioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, BangladeshBioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, BangladeshDepartment of Botany, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Botany, University of Dhaka, Dhaka, 1000, BangladeshBioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, BangladeshMolecular Biotechnology Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, BangladeshDepartment of Biochemistry and Microbiology, North South University, Bashundhara, Dhaka 1229, BangladeshMolecular Biotechnology Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh; Corresponding author.Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.http://www.sciencedirect.com/science/article/pii/S2352914823002265Alzheimer'sDexketoprofenMolecular dynamics simulationADMETIn silico |
| spellingShingle | Ishtiaque Ahammad Zeshan Mahmud Chowdhury Arittra Bhattacharjee Sheikh Sunzid Ahmed Farzana Akter Mohammad Uzzal Hossain Keshob Chandra Das Chaman Ara Keya Md. Salimullah Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease Informatics in Medicine Unlocked Alzheimer's Dexketoprofen Molecular dynamics simulation ADMET In silico |
| title | Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease |
| title_full | Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease |
| title_fullStr | Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease |
| title_full_unstemmed | Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease |
| title_short | Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease |
| title_sort | structure based pharmacological screening molecular docking and dynamic simulation reveals dexketoprofen as a repurposable drug against alzheimer s disease |
| topic | Alzheimer's Dexketoprofen Molecular dynamics simulation ADMET In silico |
| url | http://www.sciencedirect.com/science/article/pii/S2352914823002265 |
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