12 research outputs found

    Stabilization of the structures.

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    <p>RMSD plot of Cα atoms of A) <i>mut</i> (PDB: 1OSJ, A172L) and B) <i>wt</i> (PDB: 1ipd, A172) at 300 K (red) and 337 K (green).</p

    Long distance networks in A) <i>wt</i> and B) <i>mut</i>.

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    <p>A and B represents the Cα-Cα distance in <i>wt</i> and the <i>mut</i>, respectively. i, ii, iii represents the corresponding distances at 337 K (Cα-Cα<sub>337K</sub>), 300 K (Cα-Cα<sub>300K</sub>), difference in distances at 337 K and 300 K (Cα-Cα<sub>337K-300K</sub>), respectively. The regions showing extreme deviation (-1 nm) are marked with blue ovals and are represented in iii, as difference of i and ii. The temperature at which simulation is conducted is written in subscript. All residues, 1–690, are represented by their respective Cα atoms in x and y axis.</p

    Difference in average HBs of <i>mut</i> (grey) and <i>wt</i> (black) at 337 K and 300 K.

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    <p>The change in average number of HBs formed between MS, SS, MM, and IP in case of <i>mut</i> and <i>wt</i> at 337 K and 300 K are highlighted. Error bars are displayed for the selected series with 5% of the value.</p

    Difference in A) saltbridges, B) IP HBs and C) hydrophobic contacts (y-axis) based on percentage of the interaction existed (x-axis) at 337 K and 300 K in <i>mut</i> (blue) and <i>wt</i> (red) is represented by bar graphs.

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    <p>Insets in panel A, B and C represents short lived (0 < X ≤ 10%), substantially lived (10 < X ≤ 90%) and long lived (90 < X ≤ 100%) interactions. The criterion for saltbridge, IP HBs and hydrophobic contacts are mentioned in materials and methods. 5% of the series value is displayed as error bars.</p

    RMSF of all Cα atoms in A) <i>mut</i> and B) <i>wt</i> at 300 K (green) and 337 K (red) with reference to initial structure.

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    <p>Deviations more than 1 Å are highlighted with black dashed brackets. C) Deviated Cα atoms of <i>mut</i> and <i>wt</i> are shown with deviation (Å).</p

    Relative inhibitory effects of selected known and newly tested compounds against ADC.<sup>[a]</sup>

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    [a]<p>The measurements were performed using 1 mM L-aspartate, 3 µM ADC, and 1 mM compound (potential inhibitor) in D<sub>2</sub>O at 25°C.</p>[b]<p>The conversion percentage corresponds to the product formed by integration of the <sup>1</sup>H NMR signals corresponding to substrate and product of the enzymatic reaction after ca. 30 min upon addition of the enzyme. The time was adjusted to correspond to 50% conversion in the <i>absence</i> of inhibitor (reference). The absolute values were averaged from at least two independent assays.</p>[c]<p>The relative inhibitory effect, <i>k</i><sub>rel</sub>, was calculated as the ratio of the conversion percentages in the presence and absence of compound.</p>[d]<p>While full inhibition was also observed when using double the enzyme concentration, i.e., 6 µM, only a small nhibitory effect could be detected (<i>k</i><sub>rel</sub> = 0.9) when the assay was performed with 100 µM oxaloacetate, i.e., at a 10-fold lower inhibitor concentration.</p>[e]<p>A smaller <i>k</i><sub>rel</sub> value of 0.74, suggesting moderate inhibition, was observed upon preincubation with ADC for 1 h at ambient temperature.</p

    Kinetic monitoring of ADC activity carried out using 1 mM L-aspartate and 3 µM enzyme.

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    <p>The different points correspond to conversion percentages of the individual <sup>1</sup>H NMR spectra taken at increasing reaction times after initiation of the reaction in D<sub>2</sub>O at 25°C. Percentage of product formation and substrate depletion is represented by filled and empty circles, respectively. The percentage of product and substrate after 30 min of the reaction in the presence of D-tartrate is represented by filled and empty squares, respectively.</p

    Chemical structures of known inhibitors against ADC (<i>K1–K7</i>) and computationally identified potential inhibitors obtained <i>via</i> virtual screening (<i>I1–I7</i>).

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    <p>Chemical structures of known inhibitors against ADC (<i>K1–K7</i>) and computationally identified potential inhibitors obtained <i>via</i> virtual screening (<i>I1–I7</i>).</p

    Assessment of drug-like properties of the lead molecules and fumarate as verified by Qikprop (Schrodinger 9.0).

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    a<p>Ligand IDs are of the Maybridge, NCI, FDA ligand databases.</p>b<p>Molecular weight (<500 Da).</p>c<p>Hydrogen bond donors (<5).</p>d<p>Hydrogen bond acceptors (<10).</p>e<p>Predicted octanol/water partition co-efficient log p (recommended range: −2.0 to 6.5).</p>f<p>Predicted aqueous solubility; S in mol/L (acceptable range: −6.5 to 0.5).</p>g<p>Predicted IC<sub>50</sub> value for blockage of HERG K+ channels (acceptable range: above −5.0).</p>h<p>Predicted Caco-2 cell permeability in nm/s (acceptable range: 25 is poor and .500 is great).</p>i<p>Percentage of human oral absorption (<25% is poor and >80% is high).</p>j<p>Prediction of binding to human serum albumin (acceptable range: −1.5 to 1.5).</p

    Binding poses of the identified eight lead molecules with MtbADC.

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    <p>The binding modes of the proposed lead molecules are shown as ball and stick. Atoms colors are: H: white, C: green, N: blue, O: red and S: yellow. The interacting MtbADC residues are drawn as thin wireframe in the same color scheme and are labeled. Hydrogen bond interactions are shown as dotted yellow lines, along with the distance between donor and acceptor atoms. The binding pose of protein:lead molecule interactions were generated with the Maestro program in the Schrodinger software suite.</p
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