Inhibitors of the kinase IspE

TY - JOUR

T1 - Inhibitors of the kinase IspE

T2 - structure-activity relationships and co-crystal structure analysis

A1 - Hirsch,Anna K. H.

A1 - Alphey,Magnus S.

A1 - Lauw,Susan

A1 - Seet,Michael

A1 - Barandun,Luzi

A1 - Eisenreich,Wolfgang

A1 - Rohdich,Felix

A1 - Hunter,William N.

A1 - Bacher,Adelbert

A1 - Diederich,Francois

AU - Hirsch,Anna K. H.

AU - Alphey,Magnus S.

AU - Lauw,Susan

AU - Seet,Michael

AU - Barandun,Luzi

AU - Eisenreich,Wolfgang

AU - Rohdich,Felix

AU - Hunter,William N.

AU - Bacher,Adelbert

AU - Diederich,Francois

PY - 2008

Y1 - 2008

N2 - <p>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.</p>

AB - <p>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.</p>

KW - NON-MEVALONATE PATHWAY

KW - 4-(CYTIDINE 5'-DIPHOSPHO)-2-C-METHYL-D-ERYTHRITOL KINASE

KW - 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE

KW - DEOXYXYLULOSE PHOSPHATE-PATHWAY

KW - FALCIPARUM GROWTH-INHIBITORS

KW - ISOPRENOID BIOSYNTHESIS

KW - NONMEVALONATE PATHWAY

KW - ANTIMALARIAL-DRUGS

KW - 4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL KINASE

KW - NONPHOSPHATE INHIBITORS

U2 - 10.1039/b804375b

DO - 10.1039/b804375b

M1 - Article

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 15

VL - 6

SP - 2719

EP - 2730

ER -