In Silico Identification of Dual-Action Compounds Targeting TLR2 and Streptococcus mutans Proteins for the Prevention...

Background/Objectives: Early childhood caries (ECC) remains a major public health concern, with Streptococcus mutans as a primary etiological agent. Current treatments rely on broad-spectrum antimicrobials, which can disrupt the oral microbiome and promote resistance. This study applied a structure-based in silico pipeline to identify molecule modulators of Toll-like receptor 2 (TLR2), a key host receptor implicated in ECC, and to explore their binding potential against major S. mutans proteins. Methods: ECC-related genes were collected from public databases and analyzed by functional enrichment and protein-protein interaction (PPI) network analysis. Hub genes were ranked using centrality algorithms. Virtual screening on TLR2 (DrugCLIP) was followed by molecular docking of selected compounds against the TLR1/TLR2 heterodimer and 50 S. mutans proteins, complemented by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Results: Fifty-four ECC-related genes and nine hub genes were identified, with TLR2 and cathelicidin antimicrobial peptide (CAMP) as central nodes. Virtual screening yielded five lead compounds fulfilling drug-likeness and toxicity criteria. Docking to TLR1/TLR2 showed favorable binding energies, with Z7684613096 showing the most consistent binding. V026-2549 displayed the highest number of strong interactions with S. mutans targets, including dTDP-glucose 4,6-dehydratase (rmlB), NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (gapN), glucosyltransferase C (gtfC), and 5-methyltetrahydropteroyltriglutamate-homocysteine methyltransferase (metE). Conclusions: Five candidate compounds with promising dual activity against TLR1/TLR2 and S. mutans proteins were prioritized for experimental validation, including TLR2 functional assays and in vitro anti-biofilm studies.