Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China.
Interdiscip Sci. 2020 Mar;12(1):59-68. doi: 10.1007/s12539-019-00352-9. Epub 2020 Jan 1.
To inhibit hIAPP aggregation and reduce toxicity of its oligomers are one of the potential strategies for the treatment of Type 2 diabetes (T2D). It has been reported that there is an effective inhibitory effect on hIAPP aggregation by five natural flavonoids, including Genistein, Rutin, Quercetin, Epigallocatechin gallate (EGCG), and Silibinin, which are widely found in our daily food. However, the detailed mechanisms to inhibit hIAPP aggregation remain unclear. Here, we explore the mechanisms of the five flavonoids against hIAPP aggregation by molecular docking and molecular dynamics simulations. We show that these flavonoids can disaggregate Chain A and Chain B of hIAPP to reduce the extended conformation by binding with two regions of hIAPP, Leu-Ala-Asn and Asn-Val-Gly-Ser-Asn, with the inhibitory ability of Genistein > Rutin > Quercetin > EGCG > Silibinin. These five compounds exhibit a common mechanism for disaggregation of the hIAPP pentamer; that is, they loosen the two nearest peptide chains to potentially destroy the hIAPP oligomer. Mutations of eight key residues remarkably affected by the flavonoids indicate that the secondary structures of the hIAPP pentamer change from β-sheet to be random coil, thereby to destroy its structural stability; moreover, the 28th (Ser), 12th (Leu) and 32nd (Val) amino acids exhibit significant effects on structural stability of the hIAPP pentamer, providing an important hint that these amino acids can be considered as potential targets for design of new candidate inhibitors against hIAPP oligomers. This work is beneficial to understanding of mechanism of these inhibits against hIAPP aggregation and will facilitate screening, modification, and design of new inhibitors.
抑制 hIAPP 聚集并降低其寡聚物的毒性是治疗 2 型糖尿病 (T2D) 的潜在策略之一。已有报道称，五种天然类黄酮，包括染料木黄酮、芦丁、槲皮素、表没食子儿茶素没食子酸酯 (EGCG) 和水飞蓟素，对 hIAPP 聚集具有有效的抑制作用，这些类黄酮广泛存在于我们的日常食物中。然而，抑制 hIAPP 聚集的详细机制仍不清楚。在这里，我们通过分子对接和分子动力学模拟研究了这五种类黄酮对 hIAPP 聚集的抑制机制。结果表明，这些类黄酮可以通过与 hIAPP 的两个区域（Leu-Ala-Asn 和 Asn-Val-Gly-Ser-Asn）结合，使 hIAPP 的 Chain A 和 Chain B 解聚，从而减少其伸展构象，其抑制能力为染料木黄酮>芦丁>槲皮素>EGCG>水飞蓟素。这五种化合物对 hIAPP 五聚体的解聚具有共同的机制，即它们松开两个最近的肽链，从而可能破坏 hIAPP 寡聚物。八个关键残基的突变显著受类黄酮影响，表明 hIAPP 五聚体的二级结构从β-折叠变为无规卷曲，从而破坏其结构稳定性；此外，28 位（Ser）、12 位（Leu）和 32 位（Val）氨基酸对 hIAPP 五聚体的结构稳定性有显著影响，这为这些氨基酸可作为设计针对 hIAPP 寡聚物的新型候选抑制剂的潜在靶标提供了重要提示。这项工作有助于理解这些抑制剂抑制 hIAPP 聚集的机制，并将有助于筛选、修饰和设计新的抑制剂。
