Molecular Dynamics Study on the Inhibition Mechanisms of Drugs CQ1–3 for Alzheimer Amyloid-β40 Aggregation Induced by Cu2+

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• 作者：Mingyan Dong ; Haoyue Li ; Dingkun Hu ; Wei Zhao ; Xueying Zhu ; Hongqi Ai
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：May 18, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：599-614
• 全文大小：907K
• 年卷期：0
• ISSN：1948-7193

文摘

The aggregation of amyloid-β (Aβ) peptide induced by Cu²⁺ is a key factor in development of Alzheimer’s disease (AD), and metal ion chelation therapy enables treatment of AD. Three CQ_i (i = 1, 2, and 3 with R = H, Cl, and NO₂, respectively) drugs had been verified experimentally to be much stronger inhibitors than the pioneer clioquinol (CQ) in both disaggregation of Aβ₄₀ aggregate and reduction of toxicity induced by Cu²⁺ binding at low pH. Due to the multiple morphologies of Cu²⁺–Aβ₄₀ complexes produced at different pH states, we performed a series of molecular dynamics simulations to explain the structural changes and morphology characteristics as well as intrinsic disaggregation mechanisms of three Cu²⁺–Aβ₄₀ models in the presence of any of the three CQ_i drugs at both low and high pH states. Three inhibition mechanisms for CQ_i were proposed as “insertion”, “semi-insertion”, and “surface” mechanisms, based on the morphologies of CQ_i–model x (CQ_i–x, x = 1, 2, and 3) and the strengths of binding between CQ_i and the corresponding model x. The insertion mechanism was characterized by the morphology with binding strength of more than 100 kJ/mol and by CQ_i being inserted or embedded into the hydrophobic cavity of model x. In those CQ_i–x morphologies with lower binding strength, CQ_i only attaches on the surface or inserts partly into Aβ peptide. Given the evidence that the binding strength is correlated positively with the effectiveness of drug to inhibit Aβ aggregation and thus to reduce toxicity, the data of binding strength presented here can provide a reference for one to screen drugs. From the point of view of binding strength, CQ₂ is the best drug. Because of the special role of Asp23 in both Aβ aggregation and stabilizing the Aβ fibril, the generation of a H-bond between CQ₃ and Asp23 of the Aβ₄₀ peptide is believed to be responsible for CQ₃ having the strongest disaggregation capacity. Therefore, besides strong binding, stronger propensity to H-bond with Asp23 would be another key factor to be taken seriously into account in drug screens. Meanwhile, the structural characteristics of drug CQ_i itself are also worthy of attention. First, the increasing polarity from CQ₁ and CQ₂ to CQ₃ in turn results in increasing probability and strength of the interaction between the drug and the N-terminal (NT) region of Aβ₄₀, which obviously inhibits Aβ peptide aggregation induced by Cu²⁺ binding. Second, both the benzothiazole ring and phenol ring of CQ_i can overcome the activation energy barrier (∼16 kJ/mol) to rotate flexibly around the intramolecular C7–N14 bond to achieve the maximum match and interaction with the ambient Aβ₄₀ residues. Such a structural feature of CQ_i paves the new way for ones in selection and modification of a drug.