Inhibition of the MurA enzyme in Fusobacterium nucleatum by potential inhibitors identified through computational and in vitro approaches.

摘要: Fusobacterium nucleatum plays a key role in several diseases such as periodontitis, gingivitis, appendicitis, and inflammatory bowel disease (IBD). The development of antibiotic resistance by this bacterium demands novel therapeutic intervention. Our recent study has reported UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) one the potential target proteins F. nucleatum. In study, we proposed two MurA inhibitors through silico screening evaluated their mode inhibition vitro experiments. It was found that structural arrangement (inside-out α/β barrel) stabilized L/FXXXG(A) motif-based interactions. protein maintained an open or substrate-free conformation due to repulsive forces between parallelly arranged positively charged residues domain I II. conformation, identified six best compounds held interactions with substrate-binding pocket via structure-based virtual natural chemical compound libraries. However, among these, only orientin quercetin-3-O-D-glucuronide (Q3G) showed better interaction capability consistent H-bond occupancy lowest binding free energy during molecular dynamic simulations. studies evidenced mixed uncompetitive Q3G, respectively, purified protein. This explains both closed (substrate-bound) conformations MurA, Q3G conformation. Therefore, predicted on MurA–substrate complex, which highlighted its constant Cys118, phosphoenolpyruvate (PEP) interacting residue. suggests may interrupt PEP binding, thereby inhibiting activity. Thus, current discusses structure demonstrates inhibitory action compounds.