Curcumin as a potential inhibitor of TGFβ3 computational insights for breast cancer therapy

Abstract

Previous research indicates that Transforming growth factor beta-3 (TGFβ3) expression levels correlate with breast cancer metastasis, and elevated TGFβ3 levels have been linked with poor overall survival in breast cancer patients. The study used computational methods to examine curcumin's effects on TGFβ3, a chemical with antiviral and anticancer characteristics. The curcumin has low Molecular Weight 368.130 (MW) and follows Lipinski Rule, Pfizer Rule, GSK Rule, Golden Triangle, BMS Rule, zero PAINS alert and Acute Toxicity Rule with zero alert. Any drug-like contender must follow these qualities. Through molecular docking analyses, curcumin displayed favourable binding affinities at the TGFβ3 binding pocket, forming key interactions such as hydrogen bonds with residues like ASP323, ARG325, VAL333, HIS334, PRO336, LYS337, GLY393, and ARG394. 500 ns molecular dynamic simulations examined docking interactions. Molecular dynamics (MD) simulations trajectories analysis, by calculating lower structural deviation, minimal residual fluctuations, structural compactness assessment by calculating radius of gyration, surface area calculation which interact with solvent, role of hydrogen bonding, and secondary structural analyses. Furthermore, principal component, Gibbs free energy landscape and MMPBSA analysis, signifying system stability. These data suggest curcumin may inhibit TGFβ3, providing a framework for developing new compounds targeting this protein.

Keywords: Breast cancer; Curcumin; Molecular docking; Molecular dynamic simulation; Transforming growth factor β-3.

Fig. 1

Representation of molecular docking result. (A) A cartoon view of TGFB3 protein in complex with curcumin. (B) Three-dimensional representation of TGFB3-curcumin complex showing interacting residues. (C) Conserved residues of TGFB3 protein in complex with curcumin in ball stick form.

Fig. 2

Graphical representation of MD simulation result. (A) RMSD plot indicating deviation of TGFB3 protein and TGFB3-curcumin complex. (B) RMSF plot indicating residual fluctuation of TGFB3 protein and TGFB3-curcumin complex. Lower panel indicating distribution plot of (C) RMSD and (D) RMSF.

Fig. 3

Graphical representation of MD simulation result. (A) Rg plot indicating stability and compactness of TGFB3 protein and TGFB3-curcumin complex. (B) SASA plot indicating solvent accessible surface part of TGFB3 protein and TGFB3-curcumin complex form. Lower panel indicating distribution plot of (C) Rg and (D) SASA.

Fig. 4

Dynamic hydrogen bonds. (A) Intramolecular hydrogen bonds plot indicating hydrogen bonds formed within TGFB3 before and after curcumin interaction. (B) Intermolecular hydrogen bonds plot indicating bonds formed between TGFB3-curcumin complex. Lower panel indicating distribution plot of (C) Intramolecular and (D) Intermolecular hydrogen bonds formation.

Fig. 5

Secondary structure plot. The analysis shows the structural elements present in (A) TGFB3 and (B) TGFB3-curcumin complex.

Fig. 6

PCA analysis. (A) Two-dimensional conformational projections of TGFB3 and TGFB3-curcumin complex. (B) Time dependent projections of trajectories on eigenvectors.

Fig. 7

Free energy landscape of (A) TGFB3 and (B) TGFB3-curcumin complex. Lower panels indicate protein and protein-ligand complex fetched from the free-energy wells in FELs.