In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease |
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Authors: | Pham Dinh Quoc Huy Yao-Chung Yu Son Tung Ngo Tran Van Thao Chin-piao Chen Mai Suan Li Yi-Cheng Chen |
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Affiliation: | 1. Institute for Computational Science and Technology, 6 Quarter, Linh Trung Ward, Thu DucDistrict, Ho Chi Minh City, Viet Nam;2. Institute of Medical Biotechnology, Tzu Chi University, Hualien, 970, Taiwan;3. Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland;4. Department of Physics, University of Sciences at Ho Chi Minh City, 227 Nguyen Van Cu, Dist. 5, Viet Nam;5. Department of Chemistry, National Dong Hwa University, Hualien 957, Taiwan;6. Department of Medicine, Mackay Medical College, New Taipei City, 225, Taiwan |
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Abstract: | BackgroundAggregation of amyloid-beta (Aβ) has been proposed as the main cause of Alzheimer's disease (AD). Vitamin K deficiency has been linked to the pathogenesis of AD. Therefore, 15 synthesized vitamin K3 (VK3) analogues were studied for their anti-amyloidogenic activity.MethodsBiological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of Aβ, such as aggregation, free radical formation, and cell viability. Molecular dynamics simulation was used to calculate the binding affinity and mode of VK3 analogue binding to Aβ.ResultsBoth numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit Aβ aggregation and conformational conversion. The calculated inhibition constants were in the μM range for VK3-10, VK3-6, and VK3-9 which was similar to the IC50 of curcumin. Cell viability assays indicated that VK3-9 could effectively reduce free radicals and had a protective effect on cytotoxicity induced by Aβ.ConclusionsThe results clearly demonstrated that VK3 analogues could effectively inhibit Aβ aggregation and protect cells against Aβ induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD.General significanceVK3 analogues effectively inhibit Aβ aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD. |
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Keywords: | Aβ, amyloid-beta VK, vitamin K AD, Alzheimer's disease IC50, half maximal inhibitory concentration ApoE, apolipoprotein E MD, molecular dynamics MM-PBSA, molecular mechanics-Poisson&minus Boltzmann surface area SI, supplemental information DCFH-DA, dichlorofluorescein diacetate DCF, dichlorofluorescein ThT, thioflavin-T FT-IR, Fourier-transform infrared ROS, reactive oxygen species |
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