In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease

Background: Aggregation of amyloid-beta (A beta) 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. Methods: Biological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of A beta, 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 A beta. Results: Both numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit A beta aggregation and conformational conversion. The calculated inhibition constants were in the mu M 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 A beta. Conclusions: The results clearly demonstrated that VK3 analogues could effectively inhibit A beta aggregation and protect cells against A beta induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD. General significance: VK3 analogues effectively inhibit A beta aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD. (C) 2013 Elsevier B.V. All rights reserved.