In Silico Investigation of Antimicrobial Agents Targeting Enterococcus Faecalis: Using Molecular Docking, Molecular Dynamics Simulations, and MM‐GBSA Analysis

Abstract Enterococcus faecalis (E. faecalis) induced pulpal infection is a major etiological factor in the early loss of deciduous teeth. However, combined antibiotic pastes have been employed to eliminate E. faecalis , which presents notable limitations, such as the development of bacterial resistance and tooth discoloration. There exists a continuous need to design reliable and effective antimicrobial agents derived from natural sources. A library of previously synthesized, novel flavonoid and chalcone derived compounds was computationally evaluated for their inhibitory potential against E. faecalis enzymes, including dihydrofolate reductase (DHFR), β‐Ketoacyl‐acyl carrier protein synthase III (KAS III), agmatine deiminase, alanine racemase, and enterococcal surface protein (Esp), using molecular docking, molecular dynamics simulations, and binding free energy calculations. Molecular docking studies against the target enzymes identified three hit compounds with the lowest docking scores. Subsequent molecular dynamics simulations and binding free energy calculations confirmed the structural stability of these enzyme inhibitor complexes. These three hit compounds demonstrated strong binding affinities and stable interactions, underscoring their potential as lead structures for drug development targeting E. faecalis . The findings suggest that naturally derived compounds may serve as promising alternatives to conventional antimicrobial agents for treating pulpal infections.