TY - JOUR
T1 - In silico identification of novel stilbenes analogs for potential multi-targeted drugs against Alzheimer's disease
AU - Firdoos, Sundas
AU - Dai, Rongji
AU - Tahir, Rana Adnan
AU - Khan, Zahid Younas
AU - Li, Hui
AU - Zhang, Jun
AU - Ni, Junjun
AU - Quan, Zhenzhen
AU - Qing, Hong
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2023/7
Y1 - 2023/7
N2 - CONTEXT: Alzheimer's disease (AD) is a chronic progressive neurodegenerative syndrome, which adversely disturbs cognitive abilities as well as intellectual processes and frequently occurs in the elderly. Inhibition of cholinesterase is a valuable approach to upsurge acetylcholine concentrations in the brain and persuades the development of multi-targeted ligands against cholinesterases.METHODS: The current study aims to determine the binding potential accompanied by antioxidant and anti-inflammatory activities of stilbenes-designed analogs against both cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and neurotrophin targets for effective AD therapeutics. Docking results have shown that the WS6 compound exhibited the least binding energy - 10.1 kcal/mol with Acetylcholinesterase and - 7.8 kcal/mol with butyrylcholinesterase. The WS6 also showed a better binding potential with neurotrophin targets that are Brain-derived Neurotrophic Factor, Neurotrophin 4, Nerve Growth Factor, and Neurotrophin 3. The tested compounds particularly WS6 revealed significant antioxidant and anti-inflammatory activities through the comparative docking analysis with Fluorouracil and Melatonin as control drugs of antioxidants while Celecoxib and Anakinra as anti-inflammatory. The bioinformatics approaches including molecular docking calculations followed by the pharmacokinetics analysis and molecular dynamic simulations were accomplished to explore the capabilities of designed stilbenes as effective and potential leads. Root mean square deviation, root mean square fluctuations, and MM-GBSA calculations were performed through molecular dynamic simulations to extract the structural and residual variations and binding free energies through the 50-ns time scale.
AB - CONTEXT: Alzheimer's disease (AD) is a chronic progressive neurodegenerative syndrome, which adversely disturbs cognitive abilities as well as intellectual processes and frequently occurs in the elderly. Inhibition of cholinesterase is a valuable approach to upsurge acetylcholine concentrations in the brain and persuades the development of multi-targeted ligands against cholinesterases.METHODS: The current study aims to determine the binding potential accompanied by antioxidant and anti-inflammatory activities of stilbenes-designed analogs against both cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and neurotrophin targets for effective AD therapeutics. Docking results have shown that the WS6 compound exhibited the least binding energy - 10.1 kcal/mol with Acetylcholinesterase and - 7.8 kcal/mol with butyrylcholinesterase. The WS6 also showed a better binding potential with neurotrophin targets that are Brain-derived Neurotrophic Factor, Neurotrophin 4, Nerve Growth Factor, and Neurotrophin 3. The tested compounds particularly WS6 revealed significant antioxidant and anti-inflammatory activities through the comparative docking analysis with Fluorouracil and Melatonin as control drugs of antioxidants while Celecoxib and Anakinra as anti-inflammatory. The bioinformatics approaches including molecular docking calculations followed by the pharmacokinetics analysis and molecular dynamic simulations were accomplished to explore the capabilities of designed stilbenes as effective and potential leads. Root mean square deviation, root mean square fluctuations, and MM-GBSA calculations were performed through molecular dynamic simulations to extract the structural and residual variations and binding free energies through the 50-ns time scale.
KW - Humans
KW - Aged
KW - Butyrylcholinesterase
KW - Acetylcholinesterase
KW - Alzheimer Disease/drug therapy
KW - Antioxidants/pharmacology
KW - Molecular Docking Simulation
KW - Molecular dynamic simulations
KW - Alzheimer’s disease
KW - Molecular docking
KW - Neurodegenerative disorders
KW - Stilbenes
KW - Neurotrophins
KW - Bioinformatics
UR - http://www.scopus.com/inward/record.url?scp=85161799164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85161799164&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/72fbd8cb-1255-3603-800c-7207c7b5a421/
U2 - 10.1007/s00894-023-05609-1
DO - 10.1007/s00894-023-05609-1
M3 - Article
C2 - 37314512
SN - 1610-2940
VL - 29
SP - 209
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 7
M1 - 209
ER -