Molecular docking and molecular dynamic simulation studies to identify potential isoquinoline alkaloid derivatives against chorismate synthase of Listeria monocytogenes

Abstract

Listeriosis is a severe foodborne infection caused by Listeria monocytogenes, representing a major health threat particularly to immunocompromised individuals, pregnant women, and the elderly. Owing to the bacterium’s capacity for biofilm formation and its growing resistance to conventional antibiotics, the identification of novel therapeutic targets has become imperative. The shikimate pathway of L. monocytogenes, which is essential for the biosynthesis of aromatic amino acids and other metabolites required for bacterial viability, involves the key enzyme chorismate synthase (LmCS). In the present study, this enzyme was investigated as a potential drug target. Through a comprehensive in silico approach encompassing pharmacophore modeling, virtual screening, molecular docking, ADME profiling, and molecular dynamics (MD) simulations, three natural compounds— Comp_38, Comp_98, and Comp_350—were identified as potential LmCS inhibitors. ADMET analyses confirmed favorable pharmacokinetic profiles and drug-likeness consistent with Lipinski’s Rule of Five. Furthermore, MD simulations demonstrated the structural stability of the enzyme–ligand complexes throughout the simulation trajectories. Collectively, these findings highlight isoquinoline-derived compounds such as Comp_38, Comp_98, and Comp_350 as promising lead candidates for the development of novel anti-listerial agents, offering a potential new avenue to combat this resilient pathogen.