Vitamin D analog calcitriol for breast cancer therapy; an integrated drug discovery approach.
Nagaraj B SKrishnan Namboori P KKrishna Swaroop AkeySathianarayanan SankaranRajesh Kumar RamanJawahar NatarajanSelvaraj JubiePublished in: Journal of biomolecular structure & dynamics (2023)
As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.
Keyphrases
- induced apoptosis
- tyrosine kinase
- signaling pathway
- cancer therapy
- small cell lung cancer
- molecular dynamics simulations
- epidermal growth factor receptor
- cell cycle arrest
- drug discovery
- drug delivery
- drug induced
- breast cancer cells
- molecular docking
- genome wide
- endoplasmic reticulum stress
- cell proliferation
- gene expression
- pi k akt
- epithelial mesenchymal transition
- cell death
- protein protein
- zika virus
- risk assessment
- machine learning
- molecular dynamics
- squamous cell carcinoma
- oxidative stress
- working memory
- small molecule
- case control
- bioinformatics analysis
- binding protein
- dengue virus