Molecular insights into antibiofilm inhibitors of Streptococcus mutans glucosyltransferases through in silico approaches

Abstract

Streptococcus mutans, a primary cariogenic bacterium, plays a central role in dental caries, one of the most widespread chronic diseases globally. Glucosyltransferases (GTFs) are key virulence factors in this process, as they synthesize extracellular polysaccharides that contribute to biofilm formation and pathogenicity. Targeting GTFs has emerged as a promising strategy for preventing dental caries, with previous studies demonstrating its potential efficacy. This study builds on our prior work by providing detailed molecular insights into the binding modes of previously identified GTF inhibitors. Using computational tools, including density functional theory, molecular docking, and molecular dynamics simulations, we examined the binding interactions and structural stability of selected inhibitors. All investigated candidates demonstrated superior binding behavior compared to the reference ligand, acarbose, as indicated by multiple structural parameters. Structural dynamics analysis revealed significant stability in the binding interactions of Complex III and V, with average deviations of 2.06 ± 0.38 and 2.07 ± 0.30 Å, respectively. Similarly, a trend in structural compactness was observed, with gyration values of 32.98 ± 0.23 and 33.01 ± 0.24 Å, respectively. Principal component analysis indicated that the constructed pattern approaches zero with the achievement of a global energy minimum, particularly for Complex III and V. Furthermore, MM/PBSA free energy calculations identified Compound V as the most favorable binder, with a binding free energy of -24.20 kcal/mol. Our findings provide valuable molecular-level insights into the inhibitory mechanisms of GTF-targeting compounds, strengthening their potential as anti-cariogenic agents. By elucidating key binding interactions, this study contributes to the ongoing search for improved scaffolds that may hinder biofilm-mediated infections and advance therapeutic strategies against dental caries.

Keywords: Streptococcus mutans; Density functional theory; Dental caries; Free energy landscape; Molecular dynamic simulation.

Fig. 1

Visualization of HOMO-LUMO counter plots for the test compounds, providing insights into their electronic structures and potential reactivity.

Fig. 2

Mapping the 3D interaction landscape of (a) Compound I, (b) Compound II, (c) Compound III, (d) Compound IV, (e) Compound V, and (f) Compound VI within the protein’s binding site.

Fig. 3

Illustrating the time dependent RMSD of selected Compound I (red), Compound II (pink), Compound III (cyan) Compound IV (green), Compound V (orange), and Compound VI (violet) within the protein’s binding site providing insights into their structural stability. The black line represents the pattern observed for Acarbose bound to the target protein.

Fig. 4

The gyration patterns of selected compounds—Compound I (red), Compound II (pink), Compound III (cyan), Compound IV (green), Compound V (orange), and Compound VI (violet)—within the protein’s binding site during the simulation, shedding light on the folding dynamics. The black line represents the pattern observed for Acarbose bound to the target protein.

Fig. 5

The per residue fluctuation profile of the selected compounds—Compound I (red), Compound II (pink), Compound III (cyan), Compound IV (green), Compound V (orange), and Compound VI (violet)—within the protein’s binding site over the course of simulation, offering insights into their respective degrees of flexibility. The black line represents the pattern observed for Acarbose bound to the target protein.

Fig. 6

Scatter plot of principal components along with a free energy landscape observed for the GTFSI bound to (a) Acarbose, (b) Compound I, (c) Compound II, (d) Compound III, (e) Compound IV, (f) Compound V, and (g) Compound VI.

Fig. 7

The 2D structural representation of heterocyclic scaffolds against Streptococcus mutans’s biofilm.