Globally, dental caries is a prevalent oral disease caused by cariogenic bacteria, primarily Streptococcus mutans. It establishes caries either through sucrose-dependent (via glycosyltransferases) or through sucrose-independent (via surface adhesins Antigen I/II) mechanism. Sortase A (srtA) attaches virulence-associated adhesins to host tissues. Because of their importance in the formation of caries, targeting these proteins is decisive in the development of new anticariogenic drugs. High-throughput virtual screening with LIPID MAPS -a fatty acid database was performed. The selected protein-ligand complexes were subjected to molecular dynamics simulation (MDs). The Binding Free Energy of complexes was predicted using MM/PBSA. Further, the drug-likeness and pharmacokinetic properties of ligands were also analyzed. Out of 46,200 FAs scrutinized virtually against the three protein targets (viz., GtfC, Ag I/II and srtA), top 5 FAs for each protein were identified as the best hit based on interaction energies viz., hydrogen bond numbers and hydrophobic interaction. Further, two common FAs (LMFA01050418 and LMFA01040045) that showed high binding affinity against Ag I/II and srtA were selected for MDs analysis. A 100ns MDs unveiled a stable conformation. Results of Rg signified that FAs does not induce significant structural & conformational changes. SASA indicated that the complexes maintain higher thermodynamic stability during MDs. The predicted binding free energy (MM/PBSA) of complexes elucidated their stable binding interaction. ADME analysis suggested the FAs are biologically feasible as therapeutic candidates. Overall, the presented in silico data is the first of its kind in delineating FAs as promising anticaries agents of future.Communicated by Ramaswamy H. Sarma.
