Targeted Therapy Exploration against Human Dental Caries through Virtual Screening of Natural Compounds

Abstract

Glucosyltransferase (GtfC) produced by Streptococcus mutans plays a key role in dental caries development. As S. mutans consumes sugars from diet, GtfC converts these sugars into sticky glucans, which facilitate the attachment of bacteria on tooth surfaces and initiate the formation of dental plaque. The bacteria within the plaque produce acids as by-products of sugar fermentation. These acids lower the pH in the oral cavity, leading to enamel demineralization, which weakens the tooth structure and paves the way for the development of cavities. GtfC inhibition may have implications significant for oral health and prevention of dental caries by disrupting biofilm formation, reducing acid production, and lowering the cariogenic potential of oral bacteria. In this study, virtual screening has been employed to explore the potential of natural compounds as targeted therapeutic agents against dental caries. This analysis aimed to uncover natural compounds that exhibit strong binding affinities with the catalytic site residues of GtfC. The interaction analysis of top-ranked compounds A1, A2, and A3 revealed binding with the key residues involved in the transglucosylation reaction of GtfC, thereby preventing the accumulation of pathogenic biofilms and acid production responsible for enamel demineralization. These compounds were further assessed for their drug-like properties, physicochemical attributes, and potential to disrupt the glucosyl transfer reaction essential for caries initiation. Additionally, ADME (absorption, distribution, metabolism, and excretion) and toxicity assessments were performed to evaluate the pharmacokinetic and safety profiles of the identified hits. As all 3 compounds exhibit similar binding interface, molecular dynamics simulations were employed to evaluate the interaction and stability of the GtfC-A1 complex. Multiple Sequence Alignment (MSA) was performed to identify regions of GtfC sequences that are evolutionarily conserved across Streptococcus species. Homology modeling was used to predict the structures of GtfC proteins in other Streptococcus species. MSA and homology modeling across species enhanced understanding of protein structure, function, and evolution. It revealed a high conservation at catalytic site residues across species, providing insights into the GtfC interactions and potential ligand-binding capabilities. The outcomes of this study may provide valuable insights into the development of novel therapeutics for preventing dental caries and advancing oral health care.