Abstract
Steady-state fluorescence spectroscopy indicated that a ground state complex was formed between deferasirox (DFX) and pepsin. The binding parameters and thermodynamic parameters of pepsin–DFX complex formation suggested the presence of only one high affinity binding site in the binding process of DFX and pepsin and that the binding process was hydrogen bond dominated. According to the MD simulation optimal pepsin–DFX binding model analysis, the binding force between DFX and pepsin was mainly hydrogen bonding, and the hydrophobic interaction was supplemented. Synchronous fluorescence spectroscopy and 3D fluorescence spectroscopy indicated that the binding of DFX to pepsin had minor effect on the protein structure and function. Circular dichroism spectra showed that DFX had no significant effect on the main secondary structure of pepsin. MD analysis also showed that DFX did not affect the looseness of pepsin and the overall secondary structure, but it affected the amino acid residue sequence Leu48-Ala49-Cys50-Ser51-Asp52. Pepsin enzyme activity test showed that the addition of DFX had a slight enhancement effect on the activity of pepsin. Combined with the MD results, DFX bound to pepsin and was closer to the pepsin active site Asp-215, which may affect the electrical environment of Asp-215 residues and enhance the activity of pepsin.
Highlights
The drug deferasirox (DFX) (Fig. 1) is the rst oral ironloading agent approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload
This study aims to use molecular docking and molecular dynamics (MD) simulation calculation methods to obtain the binding model of drug and protein that is most consistent with the actual situation and to study the effects of DFX on the secondary structure and active site of pepsin based on the binding model
The dynamic environment of DFX and Asp-215 would affect the electrical environment of Asp-215 residues, which would have a certain effect on the function of 215-Asp. The mechanism of this interaction showed that DFX formed a ground state complex with pepsin with only one high affinity binding site for the binding of DFX to pepsin, and the binding process was dominated by hydrogen bonds
Summary
The drug deferasirox (DFX) (Fig. 1) is the rst oral ironloading agent approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload. Very few patients will have severe symptoms of gastrointestinal bleeding.[3] A er oral administration of the drug to the stomach through the mouth, the drug combines with the important digestive protease in the stomach, i.e., pepsin, thereby affecting the activity of pepsin, causing abdominal pain, nausea, vomiting, and other adverse symptoms.[4] Pepsin is the product activated by pepsinogen and is secreted by the chief cell of the gastric gland It is widely found in the gastric juice of mammals and hydrolyzes proteins in an acidic environment.[5,6] The catalytically active site of pepsin consists of two Asp, namely, Asp-32 and Asp-215. Studying the binding interaction between the drug and pepsin can provide a scienti c basis for the treatment of gastric diseases induced by drug.[8,9] Based on the abovementioned discussion, it is 37208 | RSC Adv., 2018, 8, 37208–37218
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