title: Discovery of Helicobacter pylori shikimate kinase inhibitors: bioassay and molecular modeling.
abstract: Shikimate kinase (SK) is the fifth enzyme in the shikimate pathway and catalyzes the phosphate transfer from ATP to shikimate in generating shikimate 3-phosphate and ADP. SK has been developed as a promising target for the discovery of antibacterial agents. In this report, two small molecular inhibitors (compound 1, 3-methoxy-4-{[2-({2-methoxy-4-[(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}methyl)benzyl]oxy}benzaldehyde; compound 2, 5-bromo-2-(5-{[1-(3,4-dichlorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}-2-furyl)benzoic acid) against Helicobacter pylori SK (HpSK) were successfully identified with IC(50) values of 5.5+/-1.2 and 6.4+/-0.4 microM, respectively. The inhibition kinetics shows that compound 1 is a noncompetitive inhibitor with respect to both shikimate and MgATP, and compound 2 is a competitive inhibitor toward shikimate and noncompetitive inhibitor with respect to MgATP. The surface plasmon resonance (SPR) technology based analysis reveals that the equilibrium dissociation constants (K(D)s) of compounds 1 and 2 with HpSK enzyme are 4.39 and 3.74 microM, respectively. The molecular modeling and docking of two inhibitors with HpSK reveals that the active site of HpSK is rather roomy and deep, forming an L-shape channel on the surface of the protein, and compound 1 prefers the corner area of L-shape channel, while compound 2 binds the short arm of the channel of SK in the binding interactions. It is expected that our current work might supply useful information for the development of novel SK inhibitors.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Han
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000465:Algorithms; D001681:Biological Assay; D003001:Cloning, Molecular; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D011994:Recombinant Proteins / Q000096:biosynthesis; D020349:Surface Plasmon Resonance
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase