Flavonoids as dual-action agents for anticancer and anti-tooth caries: a molecular docking and dynamics simulation on MMP2 inhibition

Abstract

Objective: Cancer pathogenesis is linked to matrix metalloproteinase-2 (MMP2). Numerous studies have indicated an elevated expression of MMP2 in the tissue microenvironment of different cancers, including breast, oral, prostate, ovarian, colorectal, bladder, lung, and hepatocellular carcinoma. The significant role of MMP2 in the degradation of organic compounds in dentin, causing dental caries, has been indicated by accumulating evidence. This study explored the possibility of using flavonoids as natural compounds capable of inhibiting MMP2 to meet the need for new and potent MMP2 inhibitors. Methods: The AutoDock software evaluated the binding energies between selected flavonoids and the MMP2 catalytic domain and ranked the ligands based on their inhibition constant (Ki) values and Gibbs free binding energy scores. The Discovery Studio Visualizer tool demonstrated how the highest-ranked flavonoids interact with the MMP2. Molecular dynamics was conducted for the most potent MMP2 inhibitor in a 100 ns computer simulation. Results: Kaempferol 3-rutinoside-7-sophoroside demonstrated an inhibitory effect against MMP2 with a Ki value and ΔGbinding score of 209.92 fM and −17.30 kcal/mol, respectively. This flavonoid was able to restrict MMP2 activity within a femtomolar range. This study identified eight flavonoids with Ki values in the picomolar range. According to the study, the docked pose of kaempferol 3-rutinoside-7-sophoroside within the MMP2 catalytic domain reached stability after a simulation of ~60 nanoseconds. Conclusion: Inhibition of MMP2 by flavonoids, notably kaempferol derivatives, might be an effective therapeutic strategy for cancer treatment.