Design and docking studies of inhibitors for the chorismate synthase from Streptococcus pneumoniae using 5-enol pyruvylshikimate 3-phosphate (EPSP) analogues

Abstract

Streptococcus pneumoniae is one of the common causes of community-acquired bacterial infection. It causes respiratory tract infections and is increasingly becoming resistant to antibacterial agents available for its treatment / management. There is therefore an urgent need for new antibacterial agents, particularly those that act on novel targets, or improvements on the agents available. Chorismate synthase (CS) is a key enzyme in the catalysis of 5- enolpyruvylshikimate 3-phosphate (EPSP) to chorismate, which is the final step in the shikimate pathway. This pathway has been shown to be absent in humans, thus making it an attractive target for potential antibacterial development. In silico docking studies were carried out on analogues of EPSP in four different active site models of CS from Streptococcus pneumoniae. Active site model 3 was found to be most appropriate for docking studies as it contained conserved active site arginines and water molecules required for EPSP binding. Four EPSP analogues were found to have higher docking scores than the natural substrate and were used to design inhibitors for CS based on substitutions on the C1 and C3- phosphate positions of CS. C3-phosphate monosubstituted molecules and C1 monosubstituted molecule were seen to have higher docking scores than the lead molecules. Disubstitution on both C1 and C3-phosphate positions resulted in molecules showing greater inhibitory potentials from their docking scores. These series of analogues will provide a starting point for further investigations into the identification of inhibitors of chorismate synthase.

Keywords: Chorismate synthase (CS); Docking studies; 5-enolpyruvylshikimate-3- phosphate (EPSP); Streptococcus pneumoniae; Flavin mononucleotide (FMN)