Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer

Area of Science:

• Pharmacology
• Biochemistry
• Computational Chemistry

Background:

• Breast cancer therapy often targets hormone receptors but faces challenges like adverse effects and resistance.
• Current treatments include Tamoxifen, Trastuzumab, and Paclitaxel, necessitating exploration of novel therapeutic agents.
• Phytochemicals offer a promising avenue for developing new anti-cancer drugs with potentially improved profiles.

Purpose of the Study:

• To investigate the potential of furanocoumarins as inhibitors of key breast cancer targets: estrogen receptor alpha (ERα), progesterone receptor (PR), epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (mTOR).
• To evaluate the drug-likeness and anti-breast cancer activity of selected furanocoumarins using computational and in vitro methods.
• To identify specific furanocoumarins with potent inhibitory actions against breast cancer-related pathways.

Main Methods:

• Molecular docking simulations using the FlexX algorithm to predict protein-ligand interactions between 23 furanocoumarins and target proteins (ERα, PR, EGFR, mTOR).
• Assessment of furanocoumarin drug-likeness using Lipinski's Rule of Five.
• In vitro antagonist and inhibition assays for ERα, EGFR, and mTOR to validate computational findings.

Main Results:

• Molecular docking identified Xanthotoxol as the lead compound with the best docking score against breast cancer targets, followed by Bergapten, Angelicin, Psoralen, and Isoimperatorin.
• In vitro assays confirmed the inhibitory and antagonist activities predicted by molecular docking, validating the computational approach.
• The study demonstrated significant anti-breast cancer potential for the tested furanocoumarins, particularly Xanthotoxol.

Conclusions:

• Selected furanocoumarins, notably Xanthotoxol, exhibit potent inhibitory effects on key breast cancer targets (ERα, EGFR, mTOR).
• The findings support the use of molecular docking and in vitro assays in identifying novel anti-cancer phytochemicals.
• These furanocoumarins represent promising candidates for further preclinical and clinical evaluation in breast cancer treatment strategies.