Abstract
Helicobacter pylori is a gram-negative gastric pathogen that colonizes approximately half of the human population and may persist in its presence for a lifetime. Enduring infection of this peculiar microbe leads to the chronic inflammation of gastric epithelial cells, which may further progress into peptic ulcers, gastric atrophy, and gastric adenocarcinoma. The treatment of H. pylori infection using high-dosage antibiotics, however, has resulted in decreased efficacy and resistance of antibiotics. The need for new antibacterial therapies to overcome the problems of the drug resistance is therefore a major concern of healthcare professionals. One potential approach towards discovering new classes of inhibitors is to target crucial proteins in bacterial but not in mammals. The shikimate pathway which involves seven sequential enzymatic steps in the conversion of erythrose 4-phosphate (E4P) and phosphoenolpyruvate (PEP) into chorismate for subsequent synthesis of aromatic compounds is unique to microbial. Enzymes of this pathway are attractive targets for the development of nontoxic antimicrobial compounds.Dehydroquinate synthase (DHQS) is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme that converts 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) into 3-dehydroquinate (DHQ). Since it catalyzes the second key step in the shikimate pathway, which is crucial for the aromatic amino acid metabolism in bacteria, fungi and plants, but not in mammals, DHQS is a potential target for new antimicrobial agents, antiparasitic agents and herbicides. The crystal structure of H. pylori DHQS complexed with NAD has been determined at 2.4-Å resolution and was found to possess an N-terminal Rossmann-fold domain and a C-terminal α-helical domain. Structural comparison reveals that the binary complex adopts an open-state conformation and shares conserved residues in the binding pocket. Virtual docking of compounds into the active site of the HpDHQS structure using the GOLD docking program led to the identification of several inhibitors. The most active compound had an IC50 value of 61 μM, which may serve as a lead for potent inhibitors.