p<i>K<sub>a</sub></i>Determination

doi:10.1002/9781118286067.ch3

Absorption and Drug Development 2012

DOI: 10.1002/9781118286067.ch3

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pK_aDetermination

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Cited by 3 publications

References 214 publications

(115 reference statements)

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Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Lomize

Pogozheva

2019

J. Chem. Inf. Model.

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Assessment of permeability is a critical step in the drug development process for selection of drug candidates with favorable ADME properties. We have developed a novel physics-based method for fast computational modeling of passive permeation of diverse classes of molecules across lipid membranes. The method is based on heterogeneous solubility−diffusion theory and operates with all-atom 3D structures of solutes and the anisotropic solvent model of the lipid bilayer characterized by transbilayer profiles of dielectric and hydrogen bonding capacity parameters. The optimal translocation pathway of a solute is determined by moving an ensemble of representative conformations of the molecule through the dioleoyl-phosphatidylcholine (DOPC) bilayer and optimizing their rotational orientations in every point of the transmembrane trajectory. The method calculates (1) the membrane-bound state of the solute molecule; (2) free energy profile of the solute along the permeation pathway; and (3) the permeability coefficient obtained by integration over the transbilayer energy profile and assuming a constant size-dependent diffusivity along the membrane normal. The accuracy of the predictions was evaluated against experimental permeability coefficients measured in pure lipid membranes (for 78 compounds, R2 was 0.88 and rmse was 1.15 log units), PAMPA-DS (for 280 compounds, R2 was 0.75 and rmse was 1.59 log units), BBB (for 182 compounds, R2 was 0.69 and rmse was 0.87 log units), and Caco-2/MDCK assays (for 165 compounds, R2 was 0.52 and rmse was 0.89 log units).

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Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Lomize

Pogozheva

2019

J. Chem. Inf. Model.

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Quantum Chemical Prediction of pK_a Values of Cationic Ion-Exchange Groups in Polymer Electrolyte Membranes

et al. 2018

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The durability of anion-exchange membranes (AEMs) in alkaline fuel cells is largely determined by the stability of anion-exchange groups. Despite continuous research efforts, the commonly employed cations still have limited stability against hydroxide that can act as a strong base and nucleophile. This work is concerned with base-catalyzed degradation of organic cations initiated by proton abstraction to form reactive ylides or carbenes. We report on the performance of 24 methods combining density functional theory and electronic structure methods with implicit solvation calculations for predicting pK a values of organic cations in water and DMSO. The most accurate computational protocols are obtained using a combination of M06-2X/6-311++G** with the SMD solvation model for water (the mean absolute error of 0.4 pK a units) and B3LYP/aug-cc-pVTZ with the IEFPCM solvation model for DMSO (the mean absolute error of 1.4 pK a units). The aqueous pK a calculation protocol is cross-validated against the experimental C–H acidity constants outside the conventional range of 0–14 pK a values. This study rationalizes alkaline degradation of imidazolium cations with C2-alkyl substituents and provides a theoretical scale of C–H acidity for potential anion-exchange groups in AEMs.

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A Potentiometric Evaluation of Stability Constants of Two-Step Overlapping Equilibria via a Bilogarithmic Hyperbolic Cosine Method

Beaumont¹,

Martín²,

Asuero³

2016

JASMI

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A bilogarithmic hyperbolic cosine method for the evaluation of overlapping formation constants at varying (or fixed) ionic strength is devised in this paper and applied to data reported in the analytical literature, i.e. succinic acid system, Cu(II)-glycine system and Ag(I)-aminobutan-1-ol system. The method is based on the linearization of the formation function ñ = f(pH) or ñ = f(pL) data. A theoretical slope of unity should be obtained thus proving the correctness of the assumed equilibria. An additional advantage of the bilogarithmic method proposed is that it provides a closed scale representation of Y and X unlike other plots. This paper forms part of an investigation into the uses of bilogarithmic methods and hyperbolic functions in parameter estimation. Methods based on the application of spectrophotometric measurements have been the subject of recent studies.

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pK_aDetermination

Cited by 3 publications

References 214 publications

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Quantum Chemical Prediction of pK_a Values of Cationic Ion-Exchange Groups in Polymer Electrolyte Membranes

A Potentiometric Evaluation of Stability Constants of Two-Step Overlapping Equilibria via a Bilogarithmic Hyperbolic Cosine Method

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pKaDetermination

Cited by 3 publications

References 214 publications

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Quantum Chemical Prediction of pKa Values of Cationic Ion-Exchange Groups in Polymer Electrolyte Membranes

A Potentiometric Evaluation of Stability Constants of Two-Step Overlapping Equilibria via a Bilogarithmic Hyperbolic Cosine Method

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Product

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About

pK_aDetermination

Quantum Chemical Prediction of pK_a Values of Cationic Ion-Exchange Groups in Polymer Electrolyte Membranes