Synergistic Structural Inhibition of MMP-9 by Natural Flavonoids: A Natural Combinatorial Therapy against Cancer

Abstract

Introduction: Cancer is the uncontrolled proliferation of cells leading to metastasis due to genetic alterations resulting in oncogenes activation and tumor suppressor genes deactivation. It is the 2nd leading cause of death across the world. MMP-9 or gelatinase B, plays an effective role in ECM degradation, normal tissue turnover, and tissue remodelling. Methods: Overexpression of MMP-9 has been studied in almost all types of cancers proving the effective role of MMP-9 in accelerating malignant conditions. Thus, targeting MMP-9 to treat cancer seems to be a potential strategy to deal with adverse pathologies of cancer. Methods: Chemotherapy and radiotherapy are frequently utilized for the treatment of cancer but are associated with diverse side effects. Flavonoids are natural compounds frequently found in plants and have been analyzed for the structural inhibition potential against MMP-9 by several researchers to develop natural treatments against cancer, but none of the flavonoids have landed into clinical use. In the present study, in-depth in-silico analysis to investigate the synergistic effects of flavonoids for structural inhibition of MMP-9 was done. The ADMET and bioactive properties analysis revealed effective drug-like properties of the considered flavonoids. Principal component analysis of ADMET and bioactive properties revealed high similarity in the chemical nature of luteolin and quercetin. Molecular docking analysis of MMP-9 with the considered flavonoids individually revealed the highest effective binding energy of luteolin. Results: Combination docking analysis of MMP-9 with different combinations of flavonoids led to the identification of two combinations including Quercetin with Genistein and Luteolin and Genistein revealing high negative binding energies of -15.48kcal/mol and -15.31kcal/mol which was significantly greater than the binding energies identified for respective ligands in individual dockings. Conclusion: Thus, the present study put forward synergistic natural flavonoid combinations against cancer via the MMP-9 inhibition approach that can be further evaluated to develop high-efficacy treatments.