Integrative Computational Identification of Non-Toxic Flavonoid Derivatives as MMP-1 Inhibitors in Breast Cancer

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.