4 research outputs found

    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

    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

    HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host–Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions

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    The host–guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]­uril was investigated in aqueous solution using the indicator displacement strategy. The binding constants (10<sup>3</sup>–10<sup>9</sup> M<sup>–1</sup>) increased with guest size, pointing to the hydrophobic effect and dispersion interactions as driving forces. The measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted to allow a comparison with state-of-the-art computational methods for predicting host–guest affinity constants. In total, three quantum-chemical (QM) data sets and two explicit-solvent molecular dynamics (MD) submissions were received. When searching for sources of uncertainty in predicting the host–guest affinities, the experimentally known hydration energies of the investigated hydrocarbons were used to test the employed solvation models (explicit solvent for MD and COSMO-RS for QM). Good correlations were obtained for both solvation models, but a rather constant offset was observed for the COSMO data, by ca. +2 kcal mol<sup>–1</sup>, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol<sup>–1</sup>). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5