Prediction of the Intrinsic Hydrogen Bond Acceptor Strength of Chemical Substances from Molecular Structure

Schwöbel, Johannes; Ebert, Ralf‐Uwe; Kühne, Ralph; Schüürmann, Gerrit

doi:10.1021/jp904812b

Cited by 41 publications

(42 citation statements)

References 28 publications

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“…Kenny 12 used the electrostatic potential as a quantum chemical descriptor for HBA strength of nitrogen bases. Schwöbel and coworkers [13][14][15][16] presented several studies, in which they demonstrate the suitability of local frontier orbital descriptors 17 for the predictive quantification of Abraham's HBA and HBD parameters of a chemically much broader range of donor and acceptor sites.…”

Section: Introductionmentioning

confidence: 99%

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

Klamt

Reinisch²,

Eckert³

et al. 2013

Phys. Chem. Chem. Phys.

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In this work, experimental hydrogen-bond (HB) enthalpies measured in previous works for a wide range of acceptor molecules in dilute mixtures of 4-fluorophenol in non-polar solvents are quantified from COSMO polarisation charge densities s of HB acceptors (HBA). As well as previously demonstrated for quantum chemically calculated HB enthalpies, a good correlation of the experimental data with the polarisation charge densities is observed, covering an extended range of HBA (O, N, S, p systems and halogens) ranging from very weak to strong hydrogen bonds. Furthermore, for the first time, a quantitative analysis of experimental HB entropies is performed for such a chemical diversity of HBA. A good quantification of these entropies is achieved using the polarisation charge density s as a descriptor in combination with the logarithm of a directional partition function O HB . This partition function covers the directional and multiplicity entropy of HBA and is based on the s-proportional HB enthalpy expression taken from COSMO-RS. As a result, the experimental HB enthalpies and free energies of the B300 HB complexes are quantified with an accuracy of B2 kJ mol À1 based on COSMO polarisation charge densities.

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Section: Introductionmentioning

confidence: 99%

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

Klamt

Reinisch²,

Eckert³

et al. 2013

Phys. Chem. Chem. Phys.

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“…Organic molecules with one relevant HB donor site and known experimental Abraham parameters A were taken as collected for our previous study 29–31. As before, molecules evolving strong intramolecular HBs, such as salicylaldehyde, and molecules undergoing tautomerism, such as diazoles, were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have introduced a quantum chemical approach for predicting both HB donor and acceptor strengths in terms of their Abraham parameters A and B . Here, only the ground‐state electronic structure of the individual molecules is considered 29–31. In addition to models based on ab initio computational chemistry, a semi‐empirical AM1 calibration had been derived for B ,31 allowing for a vast reduction in computation time and thus enabling the HB acceptor basicity screening of large‐scale chemical inventories.…”

Section: Introductionmentioning

confidence: 99%

Prediction models for the Abraham hydrogen bond donor strength: comparison of semi‐empirical,ab initio, and DFT methods

Schwöbel

Ebert

Kühne

et al. 2011

J of Physical Organic Chem

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Hydrogen bonding has a great impact on the partitioning of organic compounds in biological and environmental systems as well as on the shape and functionality of macromolecules. Electronic characteristics of single molecules, localized at the H-bond (HB) donor site, are able to estimate the donor strength in terms of the Abraham parameter A. The quantum chemically calculated properties encode electrostatic, polarizability, and charge-transfer contributions to hydrogen bonding. A recently introduced respective approach is extended to amides with more than one H atom per donor site, and adapted to the semi-empirical AM1 scheme. For 451 organic compounds covering acidic -CH, -NH-, and -OH groups, the squared correlation coefficient is 0.95 for the Hartree-Fock and density functional theory (B3LYP) level of calculation, and 0.84 with AM1. The discussion includes separate analyses for weak, moderate, and strong HB donors, a comparison with the performance of increment methods, and opportunities for consensus modeling through the combined use of increment and quantum chemical methods.where the compound parameters V, E, S, A, and B characterize various types of molecular interactions, and the coefficients v, e, s, a, b, and c encode respective properties of the specific solvent system. V is the McGowan characteristic volume, E is related to the excess molar refraction of the compound, and S is supposed to cover dipolarity and polarizability. Parameter A characterizes the HB donor strength (HB acidity), while B characterizes the HB acceptor strength (HB basicity). This communication deals with the Abraham descriptor A. Further details of the other parameters are described elsewhere. [12,13] Recently, Gilli et al. reported a new method to predict HB strengths by a pK a slide rule with separate scales for HB donors and acceptors. [14] It demonstrates the general interest in methods to predict HB donor and acceptor strengths of chemical compounds from molecular structure.A fast fragment method has been developed for the HB donor strength in the Abraham scale A, based on twodimensional (2D) topological information. [15,16] An independent form of the original model has been implemented into the ChemProp software and analyzed with respect to its prediction performance. [17,18] An updated version is available through easy-to-handle commercial ADME prediction software, [19] but the implemented Absolv module is proprietary and uses unpublished parameters. Independently from the approaches above, Sheldon et al. developed a simple fragment method, based on 41 UNIFAC (wileyonlinelibrary.com) a A min ¼ minimum of experimental A values, A mean ¼ mean of experimental A values, A max ¼ maximum of experimental A values. b In addition, the dataset contained the potentially CH-acidic compounds cinnoline, acetone, methylphenyl sulfoxide and ethylphenyl methanesulfonate; their particular experimental HB donor strength A is 0.00 (acetone A ¼ 0.04).

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“…H-bond donor and acceptor strengths of compounds were calculated based on ground state calculations using model developed by Schwçbel et al [38,39] This method enable a prediction of the Abraham H-bond donor strength directly from molecular structure and without the need for explicit analyses of H-bond donor-acceptor complexes.…”

Section: Descriptors Calculatedmentioning

confidence: 99%

“…Negative logarithm of the ionisation constant (pK a ) Schwçbel Model [38,39] H-bond donor and acceptor strength (S HBD and S HBA ) chemical was considered to have been correctly assigned if there was agreement between the decision made from the SMARTS patterns and in vivo PLD observation for the compound considered.…”

Section: Softwarementioning

confidence: 99%

In Silico Studies of the Relationship Between Chemical Structure and Drug Induced Phospholipidosis

Przybylak

Cronin

2011

Molecular Informatics

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Drug-induced phospholipidosis (PLD) is a side effect of the administration of cationic amphiphilic drugs (CADs). It is desirable to identify and screen compounds with the potential to induce PLD as early as possible in drug development. Recently, a number of in silico methods have been developed to predict PLD. These models are low-cost and high-throughput strategies; however, they produce a high number of false positive predictions. The aim of this study was to assess the predictive performance of existing in silico approaches and to develop new strategies for the rapid identification of the potential PLD-inducers. Studies on 450 chemicals confirmed the high false positive rate of prediction of models based only on log P and pKa values. Modification of the methods by incorporating structural information gave moderate improvements in the prediction performance. Therefore, a new strategy, based on molecular fragments captured by SMARTS strings was developed. These structural fragments were able to identify potential PLD-inducers and achieved a high sensitivity of 85 %. The results showed that the phospholipidosis is linked directly to the molecular structure of chemical; therefore the SMARTS pattern methodology could be used as a first line of screening of PLD potential during the drug discovery process.

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Prediction of the Intrinsic Hydrogen Bond Acceptor Strength of Chemical Substances from Molecular Structure

Cited by 41 publications

References 28 publications

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

Prediction models for the Abraham hydrogen bond donor strength: comparison of semi‐empirical,ab initio, and DFT methods

In Silico Studies of the Relationship Between Chemical Structure and Drug Induced Phospholipidosis

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