Inhibition mechanism understanding from molecular dynamics simulation of the interactions between several flavonoids...

Proton-dependent glucose transporters as important drug targets can have different protonation states and adjust their conformational state under different pHs. So based on this character, research on its inhibition mechanism is a significant work. In this article, to study its inhibitory mechanism, we performed the molecular dynamics of several classical flavonoid molecules (Three inhibitors Phloretin, Naringenin, Resveratrol. Two non-inhibitors Isoliquiritigenin, Butein) with glucose transporters under two distinct environmental pHs. The results show inhibitors occupy glucose binding sites (GLN137, ILE255, ASN256) and have strong hydrophobic interactions with proteins through core moiety (C6-Cn-C6). In addition, inhibitors had better inhibitory effects in protonation state. In contrast, non-inhibitors can not occupy glucose binding sites (GLN137, ILE255, ASN256), thus they do not have intense interactions with the protein. It is suggested that favorable inhibitors should effectively take up the glucose-binding site (GLN137, ILE255, ASN256) and limit the protein conformational changes.Communicated by Ramaswamy H. Sarma.