From phylogeny to protein dynamics: A computational hierarchical quest for potent drug identification against an emerging enteropathogen “Yersinia enterocolitica”

Abstract

Yersinia enterocolitica is an enteric bacterium categorized as the third most common cause of bacterial diarrhea in Europe. The pathogen exhibits an intrinsic resistance to several antibiotics, which is exacerbated by the absence of a vaccine. This prompts a quest for novel drug targets, to tackle the alarming threat to human health caused by multiple-drug resistant Y. enterocolitica. Subtractive proteomics have revealed that Pyridoxine 5′-phosphate synthase enzyme is a safe target for novel inhibitors, as it is involved in the pathogen's essential Pyridoxine 5′-phosphate pathway. Structure based virtual screening has led to the identification of a natural drug-like compound, 2-acetyl-3-(2-heptanamidoethyl)-1H-indol-6-yl heptanoate that demonstrated a high affinity to the enzyme active site in docking studies. Furthermore, molecular dynamics (MD) simulations in aqueous solution confirm that the compound remains stable in the enzyme's active site throughout the simulation. ASN18 was identified as playing a significant role in mediating strong hydrogen bonding and hydrophobic interactions between the compound and the enzyme active site. Binding free energy calculations using the Molecular Mechanics – Generalized Born Surface Area (MMGBSA) and WaterSwap methods also predict that the compound binds to the enzyme with high affinity. The data from the present work is encouraging and will aid in the discovery of novel antibiotics against this deadly pathogen.