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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: 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.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

The top eight scoring compounds from ZINC database.
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Related In: Results  -  Collection


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f2-pmc-7-2015-009: The top eight scoring compounds from ZINC database.

Mentions: Based on favorable MOLDOCK scores, those representing lower energy required for binding,15 a total of 20 compounds were selected for further evaluation by FAF-Drugs18 to determine which fit Lipinski’s rule of five.19 Of the 20 compounds, 9 fit the requirements, including staurosporine, a known cyclin-dependent kinase inhibitor. That a known kinase inhibitor was among the positive results of the screen validated the algorithm utilized; however, staurosporine was excluded from further analysis because its known toxicity precludes its use as an antitubercular agent. The remaining eight compounds (MOLDOCK scores ranging from –144.208 to –151.943) (Fig. 2) were evaluated further using the LIGPLOT program to determine the interactions occurring between the compounds and enzyme.20 The top-scoring compound, ZINC15707201, formed hydrogen bonds with K15 (P-loop) and van der Waals interactions with S16 (P-loop), V116, and R117 (lid domain). The other top-scoring compounds also displayed interactions with these residues, suggesting that these residues will be important points of contact for potential MtSK inhibitors.16


Selective Mycobacterium tuberculosis Shikimate Kinase Inhibitors as Potential Antibacterials.

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

The top eight scoring compounds from ZINC database.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-pmc-7-2015-009: The top eight scoring compounds from ZINC database.
Mentions: Based on favorable MOLDOCK scores, those representing lower energy required for binding,15 a total of 20 compounds were selected for further evaluation by FAF-Drugs18 to determine which fit Lipinski’s rule of five.19 Of the 20 compounds, 9 fit the requirements, including staurosporine, a known cyclin-dependent kinase inhibitor. That a known kinase inhibitor was among the positive results of the screen validated the algorithm utilized; however, staurosporine was excluded from further analysis because its known toxicity precludes its use as an antitubercular agent. The remaining eight compounds (MOLDOCK scores ranging from –144.208 to –151.943) (Fig. 2) were evaluated further using the LIGPLOT program to determine the interactions occurring between the compounds and enzyme.20 The top-scoring compound, ZINC15707201, formed hydrogen bonds with K15 (P-loop) and van der Waals interactions with S16 (P-loop), V116, and R117 (lid domain). The other top-scoring compounds also displayed interactions with these residues, suggesting that these residues will be important points of contact for potential MtSK inhibitors.16

Bottom Line: 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.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