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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

Structure of MtSK bound to shikimate and the ATP analog, 5′-adenosyl-methylene-triphosphate (ADPCP).Notes: The shikimate-binding (red) and lid (blue) domains are both shown as are the Walker-B motif (cyan), the P-loop (magenta), and the adenine-binding loop (yellow). The structures of shikimate (right) and ADPCP (left) are shown with carbons in green. PDB accession number, 1ZYU.6
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f1-pmc-7-2015-009: Structure of MtSK bound to shikimate and the ATP analog, 5′-adenosyl-methylene-triphosphate (ADPCP).Notes: The shikimate-binding (red) and lid (blue) domains are both shown as are the Walker-B motif (cyan), the P-loop (magenta), and the adenine-binding loop (yellow). The structures of shikimate (right) and ADPCP (left) are shown with carbons in green. PDB accession number, 1ZYU.6

Mentions: MtSK belongs to the nucleoside monophosphate (NMP) kinase family.6 The core of its structure (Fig. 1, PDB accession number 1ZYU, resolution 2.90 Å) is a five-stranded parallel β-sheet.6 Consistent with other family members, MtSK has a lid (residues G112–D124) and NMP-binding domain (T33–E61).6 The latter is a major contributor to shikimate binding in MtSK, and as such, is also referred to as the shikimate-binding domain.6 In addition, there is the P-loop (also referred to as the Walker A-motif) (G9–S16).7 This forms part of the binding site for ATP and ADP,8 particularly by interaction with their β- and γ-phosphates, respectively.6,9 Additionally, ATP/ADP is associated with SK through the adenine-binding loop (V148–P155). Finally, there is the Walker-B motif (V75–G80), which lies near the interface between shikimate and ATP-binding sites.7 Similar to other NMP kinases, MtSK undergoes a large conformational change upon substrate binding with the largest shifts in structure occurring in the shikimate-binding and lid domains.6,10


Selective Mycobacterium tuberculosis Shikimate Kinase Inhibitors as Potential Antibacterials.

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

Structure of MtSK bound to shikimate and the ATP analog, 5′-adenosyl-methylene-triphosphate (ADPCP).Notes: The shikimate-binding (red) and lid (blue) domains are both shown as are the Walker-B motif (cyan), the P-loop (magenta), and the adenine-binding loop (yellow). The structures of shikimate (right) and ADPCP (left) are shown with carbons in green. PDB accession number, 1ZYU.6
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-pmc-7-2015-009: Structure of MtSK bound to shikimate and the ATP analog, 5′-adenosyl-methylene-triphosphate (ADPCP).Notes: The shikimate-binding (red) and lid (blue) domains are both shown as are the Walker-B motif (cyan), the P-loop (magenta), and the adenine-binding loop (yellow). The structures of shikimate (right) and ADPCP (left) are shown with carbons in green. PDB accession number, 1ZYU.6
Mentions: MtSK belongs to the nucleoside monophosphate (NMP) kinase family.6 The core of its structure (Fig. 1, PDB accession number 1ZYU, resolution 2.90 Å) is a five-stranded parallel β-sheet.6 Consistent with other family members, MtSK has a lid (residues G112–D124) and NMP-binding domain (T33–E61).6 The latter is a major contributor to shikimate binding in MtSK, and as such, is also referred to as the shikimate-binding domain.6 In addition, there is the P-loop (also referred to as the Walker A-motif) (G9–S16).7 This forms part of the binding site for ATP and ADP,8 particularly by interaction with their β- and γ-phosphates, respectively.6,9 Additionally, ATP/ADP is associated with SK through the adenine-binding loop (V148–P155). Finally, there is the Walker-B motif (V75–G80), which lies near the interface between shikimate and ATP-binding sites.7 Similar to other NMP kinases, MtSK undergoes a large conformational change upon substrate binding with the largest shifts in structure occurring in the shikimate-binding and lid domains.6,10

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