Targeting Matrix Metalloproteinase-3 for Dental Caries Prevention Using Herbal Isolates: MMP3 Inhibition by Cinnamic Acids.

Dental caries, a prevalent infectious disease affecting teeth, ranks highest among 328 diseases, according to a 2017 Lancet study. In demineralized human dentin, matrix metalloproteinase-3 (MMP3) functions as a proteoglycanase, contributing to the degradation of proteoglycan components. This process exposes collagen fibrils, thereby facilitating the demineralization of the dentin matrix. Inhibiting MMP3 shows potential for preventing dental caries. The binding affinity of 20 cinnamic acid derivatives, namely cynarin, chlorogenic acid, rosmarinic acid, cinnamyl caffeate, phenethyl caffeate, N-p-coumaroyltyramine, caffeic acid 3-glucoside, caffeic acid phenethyl ester, roscovitine, benzyl caffeate, o-coumaric acid, artepillin C, caffeic acid, methyl caffeate, 2-methylcinnamic acid, ferulic acid, drupanin, p-coumaric acid, cinnamic acid, and sinapinic acid, to the MMP3 catalytic cleft, was assessed utilizing AutoDock 4.0. Molecular dynamics simulation was then employed to analyze the stability of backbone atoms in free MMP3, MMP3-positive control inhibitor, and MMP3 complexed with the top-ranked cinnamic acid over a 100 ns computer simulation. Four cinnamic acids demonstrated scores below -10 kcal/mol, with cynarin emerging as the most potent MMP3 inhibitor, featuring a score and inhibition constant value of -15.57 kcal/mol and 3.83 pM, respectively. The MMP3-cynarin complex exhibited stability after a 50 ns computer simulation, showing a root-mean-square deviation of 8 Å. The inhibition of MMP3 by cynarin, chlorogenic acid, rosmarinic acid, and cinnamyl caffeate holds promise as a potential preventive strategy for dental caries.