An NMR-Based Approach to the Measurement of High Log K HL Values at Low Ionic Strength. 31P NMR Study of 1,2-Diaminoethane-N,N,N′,N′-tetra(methylenephosphonic Acid) Protonation Equilibrium at pH > 12

A sequential NMR based approach is proposed for measurements of high log K values at low ionic strength. [³¹P] NMR technique is used to determine the protonation constants of 1,2-diaminoethane-N,N,N,N-tetra(methylenephosphonic acid) (EDTPH, H₈L) at 25°C in 0.1 mol-dm^–3 KNO₃ and at 37°C in 0.15 mol-dm^–3 NaCl at pH 11–14. For equilibrium L + H HL log K are found to be 13.3 (0.1) and 12.9 (0.1), respectively.     

Complexation of strontium with triisopropyl ester of dichloromethylene-bis(phosphonic acid) in water and ionic liquids

The complexation of strontium with triisopropyl ester of dichloromethylene-bis(phosphonic acid) (NaL) is examined using ³¹P NMR in water and the hydrophilic ionic liquid 1-butyl-3-methylimidazolium dicyanamide ([BMIM][N(CN)₂]):      

Stability constants of cesium complexes with 18-crown-6 in ionic liquids

The stability constants of the complex[Cs(18C6)]⁺ (18C6 is 18-crown-6 (L)) in N-butylpyridinium methyl sulfate (I) and of the complex [Cs(18C6)₂]⁺ in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (II) were measured by using ¹³³Cs NMR spectroscopy at 23°C. It was found that logK(Cs + L) in solvent I is 1.20±0.13 and logK(CsL + L) in solvent IIis 1.18±0.05. For the complex [Cs(18C6)₂]⁺, the dependence of its stability constant on the temperature in the 23–50°C range was obtained and the enthalpy change in the complexation was determined: ΔH(CsL + L)= ?47 kJ/mol. It was demonstrated that the enthalpy change is favorable for the formation of [Cs(18C6)₂]⁺, while the entropy change hinders the complexation.     

13C NMR measurements of acid-base equilibrium constants in alkaline aqueous solutions of D-glucose anomers

The concentration dissociation constants pK _c of the α and β D-glucose anomers were measured at pH 12–14 by the ¹³C NMR method. The pK _c values for L ? H_?1L + H equilibria at 25°C and an ionic strength of 1.0 mol/l (NaCl) were pK _c ^α = 12.31 ± 0.03 and pK _c ^β = 12.03 ± 0.01. Dissociation was found to shift all the spectrum lines downfield. The most probable hydroxyl group responsible for the dissociation of β-D-glucose was determined.     

Comparing the quality and predictiveness between 3D QSAR models obtained from manual and automated alignment

A set of 113 flexible cyclic urea inhibitors of human immunodeficiency virus protease (HIV-1 PR) was used to compare the quality and predictive power of CoMFA and CoMSIA models for manually or automatically aligned inhibitor set. Inhibitors that were aligned automatically with molecular docking were in agreement with information obtained from existing X-ray structures. Both alignment methods produced statistically significant CoMFA and CoMSIA models, with the best q(2) value being 0.649 and the best predictive r(2) being 0.754. The manual alignment gave statistically higher values, whereas the automated alignment gave more robust models for predicting the activities of an external inhibitor set. Both models utilized similar amino acids in the HIV-1 PR active site, supporting the idea that hydrogen bonds form between an inhibitor and the backbone carbonyl oxygens of Gly48 and Gly48' and also the backbone NH group of Asp30, Gly48, Asp29', and Gly48' of the enzyme. These results suggest that an automated inhibitor alignment can yield predictive 3D QSAR models that are well comparable to manual methods. Thus, an automated alignment method in creating 3D QSAR models is encouragable when a well-characterized structure of the target protein is available.     

Stability of crown-ether complexes with alkali-metal ions in ionic liquid-water mixed solvents

Stability constants of sodium and cesium ion complexes with 18-crown-6 (18C6) and dibenzo-18-crown-6 (DB18C6) in N-butyl-4-methyl-pyridinium tetrafluoroborate [BMP][BF₄] aqueous solutions were measured using the ²³Na and ¹³³Cs NMR technique at 23 °C. To the best of our knowledge, the estimated values of stability constants reported in this study are the first such values given for ionic liquid solutions. The cationic exchange between the free and complexed species is rapid, and only formation of the 1:1 complexes [M(18C6)]⁺ and [M(DB18C6)]⁺ (M = Na⁺, Cs⁺) were observed. The complex formation constants demonstrated a strong dependence on the [BMP][BF₄] concentration. For [M(18C6)]⁺, in solutions with a 0.33–0.70 mole fraction of water in [BMP][BF₄], lg K values are found to be more than one unit higher than the lg K values measured in pure aqueous solutions, although no information concerning the influence of [BMP][BF₄] on the complex formation selectivity could be observed. DB18C6 complexes revealed significantly lower stability under the same conditions. An extrapolation to zero water content gave the lg K = 2.42 for [Cs(18C6)]⁺ in [BMP][BF₄]. It was discovered that when added to water, [BMP][BF₄] increases the solubility of crown ethers and decreases the solubility of alkali metal nitrates. Complex formation with crown ethers enhances the solubility of alkali metal salts in [BMP][BF₄].     

Thermodynamics of cesium complexes formation with 18-crown-6 in ionic liquids

Thermodynamic data for cesium complexes formation with 18-crown-6 (18C6, L) [Cs(18C6)]⁺ in N-butyl-4-methyl-pyridinium tetrafluoroborate ([BMPy][BF₄], I), in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF₄], II) and in 1-butyl-3-methylimidazolium dicyanamide ([BMIM][N(CN)₂], III) were measured with NMR ¹³³Cs technique at 23–50 °C. The stability of cesium complex in RTILs is estimated to be in the range between water and DMFA. Stability constants for [Cs(18C6)]⁺ are found to decrease as temperature is increasing. The following values for lgK(Cs+L) and ΔH(Cs+L) at 23 °C are determined: 2.6 (0.3), ?47(1) kJ/mol (RTIL I); 2.8(0.3), ?80(3) kJ/mol (RTIL II) and 3.03 (0.08), ?47(2) kJ/mol (RTIL III). It is demonstrated that enthalpy change promotes complex formation while the corresponding change of entropy is negative and provides decomposition of [Cs(18C6)]⁺.     

BRUTUS: optimization of a grid-based similarity function for rigid-body molecular superposition. II. Description and characterization

Finding novel lead molecules is one of the primary goals in early phases of drug discovery projects. However, structurally dissimilar compounds may exhibit similar biological activity, and finding new and structurally diverse lead compounds is difficult for computer algorithms. Molecular energy fields are appropriate for finding structurally novel molecules, but they are demanding to calculate and this limits their usefulness in virtual screening of large chemical databases. In our approach, energy fields are computed only once per superposition and a simple interpolation scheme is devised to allow coarse energy field lattices having fewer grid points to be used without any significant loss of accuracy. The resulting processing speed of about 0.25 s per conformation on a 2.4 GHz Intel Pentium processor allows the method to be used for virtual screening on commonly available desktop machines. Moreover, the results indicate that grid-based superposition methods could be efficiently used for the virtual screening of compound libraries.