Investigating mechanistic insights of curcumin in blocking the Interleukin-8 signaling pathway associated with Breast Cancer: An in-silico approach

Abstract

Interleukin-8 (IL-8) is a chemokine, a type of signaling molecule that has a role in immunological responses and inflammation. In recent years, IL-8 is additionally related to cancer growth and recurrence. Breast cancer growth, progression, and metastatic development are all linked to IL-8. Breast cancer cells are known to develop faster when IL-8 stimulates their proliferation and survival. It can also cause angiogenesis, or the creation of new blood vessels, which is necessary for tumor nutrition and growth. IL-8 and curcumin have been subjects of interest in drug design, particularly in the context of inflammation-related disorders and cancer. This study aims to give an overview of the role of IL-8. Inhibitor-based treatment approaches were being used to target IL-8 with curcumin. Molecular docking method was employed to find a potential interaction to supress competitive inhibition of IL-8 with curcumin. PASS analysis and ADMET characteristics were also being carried out. In the end, IL-8 complexed with curcumin is chosen for MD simulations. Overall, our results showed that during the simulation, the complex stayed comparatively stable. It is also possible to investigate curcumin further as a possible treatment option. The combined results imply that IL-8 and their genetic alterations can be studied in precision cancer therapeutic treatments, utilizing target-driven therapy and early diagnosis.

Keywords: ADMET; FEL; IL-8 (Interleukin-8); MD simulations; Molecular Docking.

Fig. 1

The 3-D structure of IL-8 with curcumin. (A) A cartoon representation of IL-8-curcumin binding complex. (B) A 2D view of the IL-8 docking groove, displaying the binding amino acid residues with the curcumin. (C) Magnified surface view of IL-8 conserved substrate-binding pocket.

Fig. 2

Structural stability analysis. (A) RMSD graph for IL-8 in apo form and with curcumin. (B) RMSF graph for IL-8 in apo form and with curcumin. (C) and (D) in the lower panels indicates the probability as PDF.

Fig. 3

Structural compactness assessment. (A) Radius of gyration (Rg) plot for IL-8 with curcumin. (B) SASA plot for IL-8 with curcumin. (C) and (D) in the lower panels display the PDF values.

Fig. 4

Dynamics of H-bonds. (A) Time dependent intramolecular hydrogen bonds. (B) Time evolution of intermolecular hydrogen bonds. (C) Distribution of intramolecular hydrogen bonds in IL-8 and curcumin. (D) Distribution of hydrogen bonds between IL and 8 and curcumin.

Fig. 5

Time-based secondary structure creation of IL-8 before and after curcumin binding. (A) IL-8 protein alone. (B) IL-8 protein following curcumin binding.

Fig. 6

PCA evaluation. (A) 2D presentations of trajectory on eigenvectors revealed distinct projections of IL-8 over curcumin binding. (B) Time projections of trajectory on eigenvectors. The violet color represents free IL-8 values, while the orange color represents IL-8 and curcumin projection. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

The picture depicts energy maps of the systems (A) IL-8, (B) IL-8-Curcumin Complex.

Fig. 8

3D FEL maps of (A) free IL-8 (B) IL-8-Curcumin complex.