Exploring Cinnamic Acids as Potent Antimetastatic Agents for Cancer Therapy: Molecular Docking and Dynamic Simulation against MMP2

Objective. Matrix metalloproteinase-2 (MMP2) overexpression has been considered as a hallmark of tumor aggressiveness. The significant roles of MMP2 in other human disorders, such as cardiovascular diseases and dental caries, have also been demonstrated. Herein, we used in silico approaches to evaluate the binding affinity of selected cinnamic acids to the MMP2 catalytic domain. The obtained findings were subsequently juxtaposed with those attributed to oleandrin, utilized as a reference pharmaceutical agent. Methods. This research employed the AutoDock software to assess the affinity of 19 herbal compounds derived from cinnamic acid to the catalytic cleft of MMP2. The ligands attaining the most negative scores, as determined by the Gibbs free binding energy assessments, were accorded the highest rankings. The interactions between the MMP2 and cinnamic acids ranked highest were elucidated using the Discovery Studio Visualizer tool. Molecular dynamics simulations were performed to investigate the structural stability of MMP2 backbone atoms when forming complexes with both the top-ranked inhibitor from this study and a standard drug. Results. Eight cinnamic acids were indicated with ΔGbinding values less than −10 kcal/mol. Cynarin emerged as the most potent inhibitor of the enzyme, with the ΔGbinding score and inhibition constant value of −15.19 kcal/mol and 7.29 pM, respectively. The MMP2 backbone atoms achieve stability around the 20 ns mark, displaying a root mean square deviation of approximately 3.2 Å when influenced by the top-ranked cinnamic acid, the standard drug, or in their free form. Conclusion. The inhibition of MMP2 by cinnamic acids, particularly cynarin, holds promise as a valuable therapeutic strategy for various human disorders, encompassing cancer, cardiovascular conditions, and dental caries.