Insulin Complexation with Cyclodextrins-A Molecular Modeling Approach

Abstract

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5-7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule.

Keywords: AutoDock; amyloid fibrillation; complex; docking; hydroxypropyl-β-cyclodextrin; insulin; molecular modeling; sulfobutylether-β-cyclodextrin.

Figure 1

A simplified presentation of a human insulin monomer, based on the X-ray crystal structure (PDB ID: 5ENA), where only the secondary structure of the protein is shown, the A chain is marked with green and the B chain with orange, and the small red dots are the water molecules [7,8].

Figure 2

The X-ray crystal structure of a human insulin hexamer (PDB ID: 1MSO) shown from the front, side and back. In this picture the molecular surface is represented and every chain is colored with a different color (A—green, B—orange, C—purple, D—magenta) [8,9].

Figure 3

The molecular surface of the insulin molecule from the front and back, marked with small black dots are the 9 binding sites obtained from the CB-Dock, numbered in order of fervency of the parameters which appeared in the results (Marked with 1 the most fervently appeared binding site, and with 9 the most rarely appeared binding site).

Figure 4

Insulin-α-cyclodextrin complex. The insulin molecular surface is marked in white and the cyclodextrin molecules are marked with with green and red licorice.

Figure 5

Insulin-β-cyclodextrin complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 6

Insulin-γ-cyclodextrin complex. The insulin molecular surface is marked with white, and the cyclodextrin molecules are marked with green and red licorice.

Figure 7

Insulin-methyl-β-cyclodextrin (DS 6) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 8

Insulin-hydroxypropyl-β-cyclodextrin (DS 1) complex. The insulin molecular surface is marked in white and the cyclodextrin molecules are marked with green and red licorice.

Figure 9

Insulin-hydroxypropyl-β-cyclodextrin (DS 2) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 10

Insulin-hydroxypropyl-β-cyclodextrin (DS 3) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with with green and red licorice.

Figure 11

Insulin-hydroxypropyl-β-cyclodextrin (DS 4) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with with green and red licorice.

Figure 12

Insulin-sulfobutylether-β-cyclodextrin (DS 1) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 13

Insulin-sulfobutylether-β-cyclodextrin (DS 2) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 14

Insulin-sulfobutylether-β-cyclodextrin (DS 3) complex. The insulin molecular surface is marked with white and the cyclodextrin molecules are marked with green and red licorice.

Figure 15

Up, left: residue A:LEU13 entering in the cavity of the hydroxypropyl-β-cyclodextrin (DS 1). Up, right: residue B:PHE1 entering in the cavity of the α-cyclodextrin. Middle: residue B:HIS10 entering in the cavity of the sulfobutylether-β-cyclodextrin (DS 3). Down, left: residue B:TYR16 entering in the cavity of the γ-cyclodextrin. Down, right: residue B:LYS29 entering in the cavity of the hydroxypropyl-β-cyclodextrin (DS 2).

Figure 16

The most commonly occurring hydrogen bond on the A chain in the insulin molecule (in this case with the sulfobutylether-β-cyclodextrin, DS 2).

Figure 17

The most commonly occurring hydrogen bonds on the first part of the B chain in the insulin molecule (in this case with the hydroxypropyl-β-cyclodextrin, DS 2).

Figure 18

The most commonly occurring hydrogen bonds on the second part of the B chain in the insulin molecule (in this case with the hydroxypropyl-β-cyclodextrin, DS 2).