Benzimidazole-Derived ATP Analogues as Potential Glutamine Synthetase Inhibitors

Gxoyiya, Babalwa S. B.; Kaye, Perry T.; Kenyon, Colin

doi:10.1080/00397910903289263

Cited by 8 publications

(3 citation statements)

References 17 publications

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“…Recently, the synthesis has been reported for a number of proposed Mt GS inhibitors (Figure 12), all of which were designed to mimic some structural features of ATP. In total, three classes of such compounds have been described, including phosphonate esters ( 38 [51]), phosphate esters ( 39 [52]) and allopurinol ( 40 [51]) derivatives. However, at the time of writing, no studies describing the biological activity of these compounds have been reported.…”

Section: Inhibitors Of Gsmentioning

confidence: 99%

Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

Mowbray

Kathiravan²,

Pandey

et al. 2014

Molecules

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Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis.Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively-and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

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Section: Inhibitors Of Gsmentioning

confidence: 99%

Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

Mowbray

Kathiravan²,

Pandey

et al. 2014

Molecules

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“…All three enzymes depend on oligomerization to become active, given that the active site is located in between monomers. Inhibitors directed to this enzyme are currently on high demand, as can be seen by the number of recent papers dedicated to design new inhibitors of GS [14,17,18,20,21,22,23,24,26,54,55,56,57,58,59]. However, all of them are designed to act on the GS active site, lacking on specificity against one particular organism or group of organisms.…”

Section: Discussionmentioning

confidence: 99%

Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets

2016

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Abstract:Background: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs-human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)-and unravel new drugable pockets. Methods: The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software. Results and Conclusions: A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes.

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“…A plant GS inhibitor (glufosinate) is one of the most widely used herbicides across the planet . Several studies proved that bacterial GS is a promising target for the development of drugs against tuberculosis, , with already several inhibitors being designed. − The GS inhibitors obtained so far target the glutamate or the ATP binding regions, with some of them being already cocrystallized within the GS enzymes. ,,, Phosphinotricin and l -Met-S-sulfoximine are the most used inhibitors targeting the amino acids binding site, acting as transition state (TS) analogue suicide inhibitors. However, effective, these inhibitors lack selectively for specific organisms.…”

Section: Introductionmentioning

confidence: 99%

Clarifying the Catalytic Mechanism of Human Glutamine Synthetase: A QM/MM Study

2017

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Glutamine synthetase (GS) is a crucial enzyme responsible for the elimination of both neurotoxic glutamate and toxic ammonium, by combining them into glutamine. Alterations on the GS activity are associated with severe liver and neurodegenerative diseases and its absence or malformation results in death. In this work, the catalytic mechanism of human GS has been investigated with high-level QM/MM calculations, showing a two-phase reaction cycle. During phase 1, GS activates the reactants (NH and glutamate) with extreme efficiency, through NH deprotonation by E305 and glutamate phosphorylation by ATP, in two spontaneous and barrierless reactions. At phase 2, NH attacks the γ-glutamyl phosphate being concomitantly deprotonated by the leaving PO, forming the glutamine and HPO products. The second phase contains the rate limiting step, with a ΔG of 19.2 kcal·mol associated with the nucleophilic substitution of the phosphate by NH. The final reaction free energy is -34.5 kcal·mol. Both phases are exergonic, the first by -22.9 kcal·mol and the second by -11.6 kcal·mol. Direct NH attack is shown to be inefficient; the possible bases that perform the NH deprotonation were systematically investigated. Negative E305 was shown to be the only one possibly responsible for NH deprotonation. Altogether, these results provide a clear atomic level picture of the reaction cycle of GS, consistent with experimental and theoretical studies on GS of this and other organisms, and provide the necessary insights for the development of more specific therapeutic GS inhibitors.

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Benzimidazole-Derived ATP Analogues as Potential Glutamine Synthetase Inhibitors

Cited by 8 publications

References 17 publications

Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets

Clarifying the Catalytic Mechanism of Human Glutamine Synthetase: A QM/MM Study

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