Integrative Computational Identification of Non-Toxic Flavonoid Derivatives as MMP-1 Inhibitors in Breast Cancer
Vijay Aadhithya C
Department of Biotechnology, Sethu Institute of Technology, Pulloor, Virudhunagar 626 115, Tamil Nadu, India.
Praveena PL
Department of Biotechnology, Sethu Institute of Technology, Pulloor, Virudhunagar 626 115, Tamil Nadu, India.
Vanaja S
Department of Biotechnology, Sethu Institute of Technology, Pulloor, Virudhunagar 626 115, Tamil Nadu, India.
Shunmuga Priya Velu
*
Department of Biotechnology, Sethu Institute of Technology, Pulloor, Virudhunagar 626 115, Tamil Nadu, India.
*Author to whom correspondence should be addressed.
Abstract
Aims: This study aims to identify non-toxic, flavonoid-derived phytochemicals as potential inhibitors of Matrix Metalloproteinase-1 (MMP-1), a key enzyme involved in breast cancer invasion and metastasis.
Study Design: An integrative in silico approach was adopted, incorporating structure-based drug design (SBDD), network pharmacology, ADMET profiling, and toxicity prediction to discover phytochemical-based MMP-1 inhibitors.
Methodology: A total of 125 phytochemicals were selected based on their reported anti-cancer and anti-metastatic properties from Dr. Duke’s and PubChem databases. Biological activity prediction was performed using PASS software, while Molinspiration and Lipinski’s Rule of Five were used to evaluate drug-likeness. Toxicity prediction was carried out using DeepToxLab. Gene-disease association and protein interaction networks were constructed via DisGeNET, STRING, and Cytoscape. Molecular docking studies were performed using CB-Dock2, and ligand-receptor interactions were visualized in Discovery Studio.
Results: PASS analysis identified several flavonoids with high potential for anti-cancer and anti-MMP activity (Pa > 0.5). Docking studies revealed that Isohamnetin showed the strongest binding affinity to MMP-1 with a Vina score of -9.0 kcal/mol, followed by Kaempferol and Diosmetin (both -8.5 kcal/mol), and Hispidulin (-8.4 kcal/mol). Geneistein showed the weakest binding at -7.8 kcal/mol. Visualization confirmed that all compounds bound within the active site of MMP-1, forming stable interactions. These lead compounds also exhibited favorable ADME profiles and the selected compounds, including kaempferol, hispidulin, and genistein, demonstrate low carcinogenicity with high-confidence predictions, while varying levels of developmental toxicity uncertainty were observed across the compounds.
Conclusion: Flavonoid compounds like Isohamnetin, Kaempferol, and Diosmetin have shown potential as non-toxic MMP-1 inhibitors, paving the way for their preclinical development as novel breast cancer agents.
Keywords: Flavonoids, Matrix Metalloproteinase-1 (MMP-1), breast cancer metastasis, In silico drug design, network pharmacology, phytochemicals, molecular docking, ADMET profiling