Identification of shikimate kinase inhibitors among anti-Mycobacterium tuberculosis compounds by LC-MS

Simithy, Johayra; Reeve, Nathaniel; Hobrath, Judith V.; Reynolds, Robert C.; Calderón, Ángela I.

doi:10.1016/j.tube.2013.12.004

Cited by 30 publications

(65 citation statements)

References 31 publications

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“…Library of hybridized pyrazolone compounds was designed based on literature and our past research experience on pyrazolone nucleus . The designed hybridized pyrazolone compounds were screened against shikimate kinase . The mechanism of transferring phosphate group from ATP to shikimate by shikimate kinase is reported as three‐dimensional structure in apo and complex state .…”

Section: Resultsmentioning

confidence: 99%

“…From the reported structures, the complex with ADP and shikimate was selected for the docking study because the conformations of SB domain in both the states were similar . Among these three domains, the SB is responsible for large conformational changes and the analogs have shown inhibition of shikimate pathway . Shikimate is stabilized within the binding site through H‐bond interactions with residues Asp 34, Arg 58, Gly 80, and Arg 136.…”

Section: Resultsmentioning

confidence: 99%

“…The shikimate kinase enzyme inhibition studies were performed using the method described by Simithy et al , with a slight modification. Test compounds at different concentrations viz., 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 µg/mL, and 15 nM of shikimate kinase were pre‐incubated for 15 min in a micro‐centrifuge tube containing 455 µL of assay buffer (100 mM Tris‐HCl pH = 7.5, 50 mM KCl, and 5 mM MgCl 2 ) at 25°C.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis

Krishnasamy

Namasivayam

Mathew

et al. 2016

Archiv der Pharmazie

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Twenty-seven hybridized pyrazolone analogs were designed, docked, synthesized in two series and evaluated for their in vitro antimycobacterial properties. In the first series, four Schiff base derivatives, 6b, 7b, 7h, and 7i, show good antitubercular activity with minimum inhibition concentration (MIC) values in the range of 32.56-42.55 µM. In the second series, two compounds, 8b and 8c, possessed significant antitubercular activity with MIC <0.37 and <0.44 μM, respectively; they were even more potent than the standards pyrazinamide (12.99 μM), ciprofloxacin (4.82 μM), and streptomycin (5.36 μM), with a selectivity index of >630. Compounds 8b and 8c showed shikimate kinase inhibition activity at 5.84 and 6.93 µM, respectively. The activity and docking results lead to the conclusion that the compounds without double bond in the imine side chain and hydrophobic clashes at the pyrazolone end are necessary for good accommodation in the binding pocket and for imparting flexibility. All the compounds were also tested for antimicrobial activity (antibacterial and antifungal) and show highly significant activities against all the microorganisms tested.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis

Krishnasamy

Namasivayam

Mathew

et al. 2016

Archiv der Pharmazie

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“…For example, Simithy et al used LC-MS and a library of about 400 antimycobacterial compounds, which were previously found by the NIH Tuberculosis Antimicrobial Acquisition and Coordination Facility (TAACF), to identify several compounds that inhibit Mt-SK [26]. The most active compounds were 19, 20 and 21, with IC 50 values between 1.9 and 3.8 µM, and these contain an oxadiazole-amide or a 2-aminobenzothiazole moiety in their structure (Fig.…”

Section: Inhibitors Identified By Screeningmentioning

confidence: 99%

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

González‐Bello

2015

CTMC

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Abstract:The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions -cell wall, DNA, RNA, and protein biosynthesis -and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described.

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“…46 Previously, we have successfully screened a library of compounds against MtSK using a direct and selective mass spectrometry-based method and provided IC 50 values for the active compounds without the need for orthogonal testing. 47 For this report, a well characterized inhibitor of shikimate kinase from Helicobacter pylori (HpSK) 13 was chosen to validate our assay and to determine if the kinetic data generated by LC-MS supported noncompetitive inhibition as previously observed by compound 1.…”

Section: −1mentioning

confidence: 99%

Development of an ESI-LC-MS-Based Assay for Kinetic Evaluation of Mycobacterium tuberculosis Shikimate Kinase Activity and Inhibition

et al. 2015

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A simple and reliable liquid chromatography-mass spectrometry (LC-MS) assay has been developed and validated for the kinetic characterization and evaluation of inhibitors of shikimate kinase from Mycobacterium tuberculosis (MtSK), a potential target for the development of novel antitubercular drugs. This assay is based on the direct determination of the reaction product shikimate-3-phosphate (S3P) using electrospray ionization (ESI) and a quadrupole time-of-flight (Q-TOF) detector. A comparative analysis of the kinetic parameters of MtSK obtained by the LC-MS assay with those obtained by a conventional UV-assay was performed. Kinetic parameters determined by LC-MS were in excellent agreement with those obtained from the UV assay, demonstrating the accuracy, and reliability of this method. The validated assay was successfully applied to the kinetic characterization of a known inhibitor of shikimate kinase; inhibition constants and mode of inhibition were accurately delineated with LC-MS.

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Identification of shikimate kinase inhibitors among anti-Mycobacterium tuberculosis compounds by LC-MS

Cited by 30 publications

References 31 publications

Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis

Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

Development of an ESI-LC-MS-Based Assay for Kinetic Evaluation of Mycobacterium tuberculosis Shikimate Kinase Activity and Inhibition

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