Unraveling Novel Prospective Inhibitors of Streptococcus pneumoniae Chorismate Synthase by Pharmacophore Screening, Docking Analysis and Molecular Dynamics Simulation Studies

Abstract

Streptococcus pneumoniae is the major causative agent of community-acquired pneumonia, one of the main infectious diseases that causes inflammation in the alveoli and leads to significant morbidity and mortality across various age groups. Current treatments are challenged by multidrug-resistant strains of S. pneumoniae, which has led to the reemergence of pneumonia in recent years; therefore, it is pivotal to identify new drug targets. The enzyme chorismate synthase (CS), involved in the shikimate pathway of S. pneumoniae, aids in the synthesis of vital aromatic amino acids and other metabolites required for bacterial viability. The present study identifies natural compounds that can inhibit CS using an in silico approach, including pharmacophore modeling, virtual screening, molecular docking, ADME analysis, and molecular dynamics (MD) simulations. Our results suggest that the identified compounds can bind effectively to the active site of S. pneumoniae CS (SpCS), exhibiting affinities better than the known inhibitor 1-benzofuran-3-one and close to the enzyme’s natural substrate, 5-enolpyruvylshikimate-3-phosphate (EPSP). This study suggests lead natural compounds as promising candidates for further investigation as potential inhibitors for the treatment of pneumonia, offering a novel strategy to combat this resilient pathogen.