Targeting shikimate pathway: In silico analysis of phosphoenolpyruvate derivatives as inhibitors of EPSP synthase and DAHP synthase

Abstract

The shikimate pathway consists of seven enzymatic steps involved in the conversion of erythrose-4-phosphate and phosphoenolpyruvate to chorismate and also responsible to the production of aromatic amino acids, such as phenylalanine, tyrosine, and tryptophan which are essential to the bacterial metabolism. The 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS) and 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) catalyze important steps in the shikimate pathway using as substrate the phosphoenolpyruvate (PEP). Due to the importance of PEP in shikimate pathway, its structure has been investigated to develop new bioinspired competitive inhibitors against DAHPS and EPSPS. In the present study, we perform a literature survey of 28 PEP derivatives, then we analyzed the selectivity and affinity of these compounds against the EPSPS and DAHPS structures using consensual molecular docking, pharmacophore prediction, molecular dynamics (MD) simulations, and binding free energy calculations. Here, we propose consistent binding modes of the selected ligands and indicate that their structures show interesting pharmacophoric properties related to multi-targets inhibitors for both enzymes. Our computational results are supported by previous experimental findings related to the interactions of PEP derivatives with DAHPS and EPSPS structures.

Keywords: Consensual docking; Molecular docking; Molecular dynamics simulation; Phosphoenolpyruvate derivatives; Shikimate pathway.