Revealing the Mechanism of EGCG, Genistein, Rutin, Quercetin, and Silibinin Against hIAPP Aggregation via Computational Simulations

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 12 –Ala 13 –Asn 14 and Asn 31 –Val 32 –Gly 33 –Ser 34 –Asn 35 , 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.