title: Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis.
abstract: Enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are therapeutic targets for the treatment of important infectious diseases. Whereas this pathway is absent in humans, it is used by plants, many eubacteria and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis. Herein, we report on the design, preparation and biological evaluation of a new series of ligands for IspE protein, a kinase from this pathway. These inhibitors were developed for the inhibition of IspE from Escherichia coli, using structure-based design approaches. Structure-activity relationships (SARs) and a co-crystal structure of Aquifex aeolicus IspE bound to a representative inhibitor validate the proposed binding mode. The crystal structure shows that the ligand binds in the substrate-rather than the adenosine 5'-triphosphate (ATP)-binding pocket. As predicted, a cyclopropyl substituent occupies a small cavity not used by the substrate. The optimal volume occupancy of this cavity is explored in detail. In the co-crystal structure, a diphosphate anion binds to the Gly-rich loop, which normally accepts the triphosphate moiety of ATP. This structure provides useful insights for future structure-based developments of inhibitors for the parasite enzymes.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, HCI, CH-8093, Zürich, Switzerland.
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Alphey
authors.forename: Susan
authors.initials: S
authors.lastname: Lauw
authors.forename: Michael
authors.initials: M
authors.lastname: Seet
authors.forename: Luzi
authors.initials: L
authors.lastname: Barandun
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisenreich
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.forename: William N
authors.initials: WN
authors.lastname: Hunter
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D008024:Ligands; D017853:Phosphotransferases (Alcohol Group Acceptor); C404502:IspE protein, E coli