@article{2cbf447e031343258656ffbb55d4431e,
title = "Computational Evaluation of Interaction between Curcumin Derivatives and Amyloid-β Monomers and Fibrils: Relevance to Alzheimer's Disease",
abstract = "BACKGROUND: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties.OBJECTIVE: To computationally assess the interaction between Aβ peptide and a set of curcumin derivatives previously explored in experimental assays.METHODS: The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms.RESULTS: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation.CONCLUSION: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.",
keywords = "Alzheimer's disease, AutoDock 4, AutoDock Vina, Aβ monomer, Aβ42 fibril, Smina, curcumin, curcumin derivatives, molecular docking, Molecular Docking Simulation/methods, Protein Structure, Secondary, Amyloid/chemistry, Humans, Protein Binding/physiology, Molecular Dynamics Simulation, Amyloid beta-Peptides/chemistry, Computer Simulation, Alzheimer Disease/metabolism, Curcumin/chemistry",
author = "Adrian Orjuela and Johant Lakey-Beitia and Randy Mojica-Flores and Hegde, {Muralidhar L.} and Isaias Lans and Jorge Al{\'i}-Torres and Rao, {K. S.}",
note = "Funding Information: M.L.H. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Ageing (NIA) of the National Institutes of Health (NIH) (award numbers R01NS088645, RF1NS112719, R03AG064266), and Houston Methodist Research Institute funds. Funding Information: Molecular docking is a valuable tool in identifying a novel anti-amyloidogenic molecule/structural derivative with therapeutic properties against AD. A combination of MD and molecular docking simulations were used to evaluate curcumin and its derivatives for their interaction with Aβ. Results showed that a single substitution on curcumin is better than a double substitution to improve the interaction of the ligands with the Aβ monomer. A relationship between molecular docking and experimental results were found. Molecular docking is important to design new molecules with neuroprotective potential. In addition, this powerful tool improves J.L-B, and K.S.R. are grateful to Melo Brain Grant, MEF Nutritional Grant for support and INDICASAT Internal Grant. JL-B. and K.S.R. also thankful to the National Science System (SNI) of National Secretariat for Science, Technology, and Innovation of Panama (SENACYT) for support. J.L-B is grateful to IBRO{\textquoteright}s LARC for short stay grant in Universi-dad Nacional de Colombia. J.A-T thanks DIB-UNAL for financial support. A.O. is grateful to International Brain Research (IBRO) and INDICASAT for the funding to participate in the molecular modeling workshops in Panama City. Funding Information: This research was funded by: National Secretariat for Science, Technology, and Innovation of Panama (SENACYT) grant number [FID17–002], INDICASAT Internal Grant [JR04-2020], International Brain Research of Latin America Regional Committee Organization (IBRO{\textquoteright}s LARC) for short stay grant in Universidad Nacional de Colombia. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Publisher Copyright: {\textcopyright} 2021 - IOS Press. All rights reserved.",
year = "2021",
doi = "10.3233/JAD-200941",
language = "English (US)",
volume = "82",
pages = "S321--S333",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press BV",
number = "s1",
}