Molecular docking analysis of nuclear factor-κB and genistein interaction in the context of breast cancer.

Vidya Mukund,Ganji Purnachandra Nagaraju,Santosh Kumar Behera,Afroz Alam

doi:10.6026/97320630015011

Vidya Mukund, Ganji Purnachandra Nagaraju + Show 2 more

Open Access

https://doi.org/10.6026/97320630015011

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Abstract

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor and it contributes to breast cancer growth and metastasis. Hence, NF-κB is considered as a target for anti-breast cancer drugs. NF-κB was retrieved from the UniProtKB Data Base with UniProt ID P19838, its energy was minimized and subjected to molecular dynamic simulations using Gromacs v5.0.7 software with GROMOS96 43A1 force field implementing the steepest descent algorithm. The structure of genistein was retrieved from NCBI PubChem database in .sdf format and convert to .pdb format. The genistein compound was docked into the active site of NF-κB proteins with AutoDock tools 1.5. The genistein compound displayed the best binding energies at -6.29 (NF-κB) kcal/mol correspondingly. The binding interactions of this compound with the active site of NF-κB proteins suggested that amino acid residues (Lys52, Ser243, Asp274, Lys, 275) might play a key role in anti-breast cancer activity. Genistein also inhibited the translocation and expression of NF-κB in the nucleus of both breast cancer cell lines. These findings might increase our understanding of the molecular and functional role of NF-κB in breast cancer. It could also help in developing additional druggable NF-κB inhibitors with high potency, specificity and outstanding bioavailability.

Highlights

Breast cancer is considered to be one of the most lethal disease in women and is the second leading cause of cancer-related deaths in the United States [1]
To gauge the dynamics and stability of each system, root mean square deviation (RMSD) profile, radius of gyration (Rg), Cα-root mean square fluctuation (RMSF), and intermolecular H-bonds were analyzed from the resultant Molecular Dynamics (MD) trajectories using GROMACS utility toolkits
To validate the results obtained from RMSD graph, we further calculated the fluctuation of residues using Root mean square fluctuation (RMSF)

Summary

Introduction

Breast cancer is considered to be one of the most lethal disease in women and is the second leading cause of cancer-related deaths in the United States [1]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is an important gene regulator, which plays a vital role in activation and progression of many cancers including breast cancer [2]. Inhibiting the activities of NF-κB in breast tumorigenesis would serve as a novel therapeutic strategy in breast cancer treatment. Genistein is a chemopreventive agent, which competes with estradiol for binding with estrogen receptor as weak estrogen [4]. It aids in regulating signal transduction as protein tyrosine kinase inhibitor and inhibits cellular oxidative stress as well as angiogenesis [5,6]. Targeting NF-κB activity inhibition may serve as a novel approach through which, genistein suppresses the breast cancer growth and progression

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