12 research outputs found
Synthesis of 2-amino-4H-chromen-4-ylphosphonates and β-phosphonomalonates via tandem Knoevenagel–Phospha-Michael reaction and antimicrobial evaluation of newly synthesized β-phosphonomalonates
Full text linkHigh-throughput screen identifies small molecule inhibitors targeting acetyltransferase activity of Mycobacterium tuberculosis GlmU
Full text linkBenzothiazole Derivative as a Novel <i>Mycobacterium tuberculosis</i> Shikimate Kinase Inhibitor: Identification and Elucidation of Its Allosteric Mode of Inhibition
Full text linkErratum to: Discovery of new Mycobacterium tuberculosis proteasome inhibitors using a knowledge-based computational screening approach
Full text linkEscherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus
No full textIsolation and Quantification of Alternariols from Endophytic Fungus,<i>Alternaria alternata</i>: LC-ESI-MS/MS Analysis
Full text linkDiscovery of new {\varvec{Mycobacterium~tuberculosis}} M y c o b a c t e r i u m t u b e r c u l o s i s proteasome inhibitors using a knowledge-based computational screening approach
Full text linkIdentification and characterization of novel small molecule inhibitors of the acetyltransferase activity of Escherichia coli N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU)
Full text linkA new class of bactericidal agents against S. aureus, MRSA and VRE derived from bisindolylmethane
Full text linkBenzothiazole Derivative as a Novel <i>Mycobacterium tuberculosis</i> Shikimate Kinase Inhibitor: Identification and Elucidation of Its Allosteric Mode of Inhibition
No full text<i>Mycobacterium tuberculosis</i> shikimate kinase (Mtb-SK)
is a key enzyme involved in the biosynthesis of aromatic amino acids
through the shikimate pathway. Since it is proven to be essential
for the survival of the microbe and is absent from mammals, it is
a promising target for anti-TB drug discovery. In this study, a combined
approach of <i>in silico</i> similarity search and pharmacophore
building using already reported inhibitors was used to screen a procured
library of 20,000 compounds of the commercially available ChemBridge
database. From the <i>in silico</i> screening, 15 hits were
identified, and these hits were evaluated <i>in vitro</i> for Mtb-SK enzyme inhibition. Two compounds presented significant
enzyme inhibition with IC<sub>50</sub> values of 10.69 ± 0.9
and 46.22 ± 1.2 μM. The best hit was then evaluated for
the <i>in vitro</i> mode of inhibition where it came out
to be an uncompetitive and noncompetitive inhibitor with respect to
shikimate (SKM) and ATP, respectively, suggesting its binding at an
allosteric site. Potential binding sites of Mtb-SK were identified
which confirmed the presence of an allosteric binding pocket apart
from the ATP and SKM binding sites. The docking simulations were performed
at this pocket in order to find the mode of binding of the best hit
in the presence of substrates and the products of the enzymatic reaction.
Molecular dynamics (MD) simulations elucidated the probability of
inhibitor binding at the allosteric site in the presence of ADP and
shikimate-3-phosphate (S-3-P), that is, after the formation of products
of the reaction. The inhibitor binding may prevent the release of
the product from Mtb-SK, thereby inhibiting its activity. The binding
stability and the key residue interactions of the inhibitor to this
product complex were also revealed by the MD simulations. Residues
ARG43, ILE45, and PHE57 were identified as crucial that were involved
in interactions with the best hit. This is the first report of an
allosteric binding site of Mtb-SK, which could largely address the
selectivity issue associated with kinase inhibitors
