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Selective Mycobacterium tuberculosis Shikimate Kinase Inhibitors as Potential Antibacterials.

Gordon S, Simithy J, Goodwin DC, Calderón AI - Perspect Medicin Chem (2015)

Bottom Line: Many studies have used in silico technology to identify compounds that are anticipated to interact with and inhibit SK.To a much more limited extent, SK inhibition has been evaluated by in vitro methods with purified enzyme.In this review, we present a summary of the progress of SK inhibitor discovery and evaluation with particular attention toward development of new antitubercular agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

ABSTRACT
Owing to the persistence of tuberculosis (TB) as well as the emergence of multidrug-resistant and extensively drug-resistant (XDR) forms of the disease, the development of new antitubercular drugs is crucial. Developing inhibitors of shikimate kinase (SK) in the shikimate pathway will provide a selective target for antitubercular agents. Many studies have used in silico technology to identify compounds that are anticipated to interact with and inhibit SK. To a much more limited extent, SK inhibition has been evaluated by in vitro methods with purified enzyme. Currently, there are no data on in vivo activity of Mycobacterium tuberculosis shikimate kinase (MtSK) inhibitors available in the literature. In this review, we present a summary of the progress of SK inhibitor discovery and evaluation with particular attention toward development of new antitubercular agents.

No MeSH data available.


Related in: MedlinePlus

Staurosporine, compound 669.
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f5-pmc-7-2015-009: Staurosporine, compound 669.

Mentions: The UF-LC/MS assay was used to measure the extent of MtSK binding when 1 μM enzyme and 1 μM inhibitor were incubated together. The binding affinities inferred from the data were 671 > 672 > 670 > 669. The LC/MS functional assay was then used to measure the extent of inhibition each compound displayed. The compounds were tested at varying concentrations, ranging from 0.05 μM to 1 μM, with 1 μM MtSK and 2 μM shikimic acid. The amount of S3P formed was measured at each concentration, and EC50 values were determined. All four of the compounds showed complete inhibition at 1 μM of inhibitor. The EC50 values for compounds 669, 670, 671, and 672 were determined to be 0.03, 0.24, 0.07, and 0.18 μM, respectively (Fig. 5).31


Selective Mycobacterium tuberculosis Shikimate Kinase Inhibitors as Potential Antibacterials.

Gordon S, Simithy J, Goodwin DC, Calderón AI - Perspect Medicin Chem (2015)

Staurosporine, compound 669.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4362912&req=5

f5-pmc-7-2015-009: Staurosporine, compound 669.
Mentions: The UF-LC/MS assay was used to measure the extent of MtSK binding when 1 μM enzyme and 1 μM inhibitor were incubated together. The binding affinities inferred from the data were 671 > 672 > 670 > 669. The LC/MS functional assay was then used to measure the extent of inhibition each compound displayed. The compounds were tested at varying concentrations, ranging from 0.05 μM to 1 μM, with 1 μM MtSK and 2 μM shikimic acid. The amount of S3P formed was measured at each concentration, and EC50 values were determined. All four of the compounds showed complete inhibition at 1 μM of inhibitor. The EC50 values for compounds 669, 670, 671, and 672 were determined to be 0.03, 0.24, 0.07, and 0.18 μM, respectively (Fig. 5).31

Bottom Line: Many studies have used in silico technology to identify compounds that are anticipated to interact with and inhibit SK.To a much more limited extent, SK inhibition has been evaluated by in vitro methods with purified enzyme.In this review, we present a summary of the progress of SK inhibitor discovery and evaluation with particular attention toward development of new antitubercular agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

ABSTRACT
Owing to the persistence of tuberculosis (TB) as well as the emergence of multidrug-resistant and extensively drug-resistant (XDR) forms of the disease, the development of new antitubercular drugs is crucial. Developing inhibitors of shikimate kinase (SK) in the shikimate pathway will provide a selective target for antitubercular agents. Many studies have used in silico technology to identify compounds that are anticipated to interact with and inhibit SK. To a much more limited extent, SK inhibition has been evaluated by in vitro methods with purified enzyme. Currently, there are no data on in vivo activity of Mycobacterium tuberculosis shikimate kinase (MtSK) inhibitors available in the literature. In this review, we present a summary of the progress of SK inhibitor discovery and evaluation with particular attention toward development of new antitubercular agents.

No MeSH data available.


Related in: MedlinePlus