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, Leu₁₂–Ala₁₃–Asn₁₄ and Asn₃₁–Val₃₂–Gly₃₃–Ser₃₄–Asn₃₅, 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聚集并降低其低聚物的毒性是治疗2型糖尿病（T2D）的潜在策略之一。据报道，在我们的日常食物中广泛发现的五种天然类黄酮对hIAPP聚集具有有效的抑制作用，其中包括染料木黄酮，芦丁，槲皮素，表没食子儿茶素没食子酸酯（EGCG）和水飞蓟宾。但是，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探索了五种类黄酮对抗hIAPP聚集的机制。我们显示这些类黄酮可以通过与hIAPP的两个区域结合，从而减少hIAPP的A链和B链，从而减少延伸的构象，Leu ₁₂ –Ala ₁₃ –Asn ₁₄和Asn ₃₁ –Val ₃₂ –Gly ₃₃ –Ser ₃₄ –Asn ₃₅，具有染料木黄酮>芦丁>槲皮素> EGCG>水飞蓟宾的抑制能力。这五种化合物显示出hIAPP五聚体解聚的共同机制。也就是说，它们使两条最接近的肽链松弛，从而可能破坏hIAPP寡聚物。类黄酮显着影响八个关键残基的突变，表明hIAPP五聚体的二级结构从β-折叠变为无规卷曲，从而破坏了其结构稳定性。此外，第28（Ser），第12（Leu）和第32（Val）氨基酸对hIAPP五聚体的结构稳定性显示出显著作用，这提供了重要提示，这些氨基酸可被视为设计新候选抑制剂的潜在靶标对抗hIAPP低聚物。