In silico exploration of Neohesperidin inhibitory mechanism on TGFpathway and improving its bioavailability

Neohesperidin, a natural compound obtained from orange, which is widely used as an industrial sweetener, has proven anti-cancer and anti-inflammatory properties but has a low bioavailability and unknown functional mechanism. Some papers have shown that Neohesperidin can prevent the phosphorylation and oligomerization of SMAD proteins in the TGF pathway, however, the detailed molecular mechanism of the process is largely unexplored. In this research, we investigated the mechanism of the effect of Neohesperidin on the intracellular domain kinase of TGF membrane receptor type ۲ and the inhibitory effect of this molecule on SMAD protein phosphorylation, Also, using peptide-drug conjugate technology, we designed a peptide structure to increase the bioavailability of this compound for the intracellular target. Materials and Methods:The SMAD protein structure and, TGF type ۲ intracellular kinase domain structure were obtained from the PDB database. The ۳D conformer of Neohesperidin was also achieved from the PubChem database. The interactions between the SMAD protein and TGF type ۲ kinase domain were investigated through the ClusPro docking web server, and the interaction between Neohesperidin and this kinase domain was explored through Molegro molecular docking software. After confirming the binding of Neohesperidin to the active site of the second TGF kinase and intending to increase the bioavailability of this compound, we designed a peptide-drug structure using HyperChem software.Results:As expected, the results of docking simulation analysis between SMAD and TGF type ۲ kinase domain, show that the SMAD carboxyl terminal is entirely placed in the kinase domain active site. The analysis of the interaction of SIS۳ and Neohesperidin with the kinase domain also shows that these molecules occupy the kinase active site with relatively similar binding sites and energy. The result from the OPM server also suggests that designed Neohesperidin-peptide conjugates have a membrane binding capability. Conclusion:The results of this study demonstrate that the Neohesperidin molecule, as a natural compound, can bind to the TGF type ۲ receptor with the same energy and site as its chemical counterpart, SIS۳, to block the kinase functional region and prevent the phosphorylation of the SMAD carboxyl-terminal. On the other hand, the peptide-drug conjugate stability and membrane binding capability show this structure’s probable potential to improve the compound bioavailability. These results provide the basis for the design of new pharmaceutical compounds based on Neohesperidin. It also suggests an approach for the optimal transfer of this compound to cells.

کلیدواژه ها:

cancer ، natural compound ، peptide