Acid-base Dissociation Constants Research Articles

Graph transformer based transfer learning for aqueous pKa prediction of organic small molecules

The acid-base dissociation constant (pKa) is an essential physicochemical parameter that indicates the extent of proton dissociation. However, accurately predicting pKa values is still challenging due to limited data availability for organic small molecules in aqueous solutions. In this work, we propose an open-source pKa prediction tool based on Graph Transformer, which combines the graph neural network and transformer to take both local and global information into account. To address the limitation of data scarcity, the experimental dataset is expanded, while transfer learning is employed by pre-training on the ChEMBL (computational) dataset and fine-tuning on the experimental dataset. The performance and generalization of the obtained models are comprehensively evaluated on both internal and external test sets. Additionally, two exemplary applications, namely the screening of tertiary amines for CO2 absorption and acidic ionic liquids for reactive extraction, are investigated to validate the reliability of our tool. The results show that our model can effectively guide the identification of promising candidates for the target applications by achieving accurate pKa predictions.

GR-pKa: a message-passing neural network with retention mechanism for pKa prediction.

During the drug discovery and design process, the acid-base dissociation constant (pKa) of a molecule is critically emphasized due to its crucial role in influencing the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and biological activity. However, the experimental determination of pKa values is often laborious and complex. Moreover, existing prediction methods exhibit limitations in both the quantity and quality of the training data, as well as in their capacity to handle the complex structural and physicochemical properties of compounds, consequently impeding accuracy and generalization. Therefore, developing a method that can quickly and accurately predict molecular pKa values will to some extent help the structural modification of molecules, and thus assist the development process of new drugs. In this study, we developed a cutting-edge pKa prediction model named GR-pKa (Graph Retention pKa), leveraging a message-passing neural network and employing a multi-fidelity learning strategy to accurately predict molecular pKa values. The GR-pKa model incorporates five quantum mechanical properties related to molecular thermodynamics and dynamics as key features to characterize molecules. Notably, we originally introduced the novel retention mechanism into the message-passing phase, which significantly improves the model's ability to capture and update molecular information. Our GR-pKa model outperforms several state-of-the-art models in predicting macro-pKa values, achieving impressive results with a low mean absolute error of 0.490 and root mean square error of 0.588, and a high R2 of 0.937 on the SAMPL7 dataset.

The role of physicochemical and topological parameters in drug design

Quantitative structure activity relationship (QSAR) is a widely used tool in rational drug design that establishes relationships between the physicochemical and topological descriptors of ligands and their biological activities. Obtained QSAR models help identify descriptors that play pivotal roles in the biological activity of ligands. This not only helps the prediction of new compounds with desirable biological activities but also helps with the design of new compounds with better activities and low toxicities. QSAR commonly uses lipophilicity (logP), hydrophobicity (logD), water solubility (logS), the acid–base dissociation constant (pKa), the dipole moment, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), molecular weight (MW), molar volume (MV), molar refractivity (MR), and the kappa index as physicochemical parameters. Some commonly used topological indices in QSAR are the Wiener index, Platt index, Hosoya index, Zagreb indices, Balaban index, and E-state index. This review presents a brief description of the significance of the most extensively used physicochemical and topological parameters in drug design.

Towards the "Eldorado" of pKa Determination: A Reliable and Rapid DFT Model.

The selection of a "perfect tool" for the theoretical determination of acid-base dissociation constants (Ka) is still puzzling. Recently, we developed a user-friendly model exploiting CAM-B3LYP for determining pKa with impressive reliability. Herein, a new challenge is faced, examining a panel of functionals belonging to different rungs of the "Jacob's ladder" organization, which classifies functionals according to their level of theory. Specifically, meta-generalized gradient approximations (GGAs), hybrid-GGAs, and the more complex range-separated hybrid (RSH)-GGAs were investigated in predicting the pKa of differently substituted carboxylic acids. Therefore, CAM-B3LYP, WB97XD, B3PW91, PBE1PBE, PBEPBE and TPSSTPSS were used, with 6-311G+(d,p) as the basis set and the solvation model based on density (SMD). CAM-B3LYP showed the lowest mean absolute error value (MAE = 0.23) with relatively high processing time. PBE1PBE and B3PW91 provided satisfactory predictions (MAE = 0.34 and 0.38, respectively) with moderate computational time cost, while PBEPBE, TPSSTPSS and WB97XD led to unreliable results (MAE > 1). These findings validate the reliability of our model in predicting carboxylic acids pKa, with MAE well below 0.5 units, using a simplistic theoretical level and a low-cost computational approach.

Significance of Histidine Hydrogen-Deuterium Exchange Mass Spectrometry in Protein Structural Biology.

Histidine residues play crucial roles in shaping the function and structure of proteins due to their unique ability to act as both acids and bases. In other words, they can serve as proton donors and acceptors at physiological pH. This exceptional property is attributed to the side-chain imidazole ring of histidine residues. Consequently, determining the acid-base dissociation constant (Ka) of histidine imidazole rings in proteins often yields valuable insights into protein functions. Significant efforts have been dedicated to measuring the pKa values of histidine residues in various proteins, with nuclear magnetic resonance (NMR) spectroscopy being the most commonly used technique. However, NMR-based methods encounter challenges in assigning signals to individual imidazole rings and require a substantial amount of proteins. To address these issues associated with NMR-based approaches, a mass-spectrometry-based method known as histidine hydrogen-deuterium exchange mass spectrometry (His-HDX-MS) has been developed. This technique not only determines the pKa values of histidine imidazole groups but also quantifies their solvent accessibility. His-HDX-MS has proven effective across diverse proteins, showcasing its utility. This review aims to clarify the fundamental principles of His-HDX-MS, detail the experimental workflow, explain data analysis procedures and provide guidance for interpreting the obtained results.

First principle determination of stability constants of metal complexes by cellmetry method

AbstractThe stability constants of 81 metal complexes were calculated using the newly‐developed method which was previously used for determining pK values of acid–base dissociation constants by plane wave functions. Fifteen metal ions and 36 ligands were chosen, and a wide range of the complexes was studied to calculate the logK and logß stability constants. The large variety of geometries and coordination modes allowed us to see the limitation of the method. In some cases, good agreements could be found with the experimental data with an accuracy of .5–1 unit. Results howed that for smaller structural changes, the stability constants can be calculated easily by using the determined parameters. For larger structural differences, rough estimations by 2–4 logK units can be conducted. Correlations could be found among the data which can help further studies as well as aid in the prediction of some unknown complexes. The pK of a hexaaqua metal complex was determined as well.

MF-SuP-pKa: Multi-fidelity modeling with subgraph pooling mechanism for pKa prediction.

Acid-base dissociation constant (pKa) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for pKa prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-pKa (multi-fidelity modeling with subgraph pooling for pKa prediction), a novel pKa prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledge-aware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-pKa prediction. To overcome the scarcity of accurate pKa data, low-fidelity data (computational pKa) was used to fit the high-fidelity data (experimental pKa) through transfer learning. The final MF-SuP-pKa model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-pKa achieves superior performances to the state-of-the-art pKa prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-pKa achieves 23.83% and 20.12% improvement in terms of mean absolute error (MAE) on the acidic and basic sets, respectively.

SO2 – Am (KOH) – TROPEOLIN OOO – H2O (Am – ETHANOLAMINES, MORPHOLINE) SYSTEMS ACID-BASE PROPERTIES

The study of data on acid-base properties of model systems SO2 – KOH – TrOOO – H2O and SO2 – Am – TrOOO – H2O (TrOOO – tropeoline OOO; Am – diethanolamine (DEA), triethanolamine (TEA), N‑methylmonoethanolamine (MMEA) and morpholine (Mf) at 293 K using pH-, spectrophotometry and colorimetry methods are presented. There is a pronounced isosbestic point at 415 nm in the electronic absorption spectra of the systems SO2– Am –TrOOO– H2O (Am = MMEA, MEA and TEA; pH ≤ 7.5; T = 293 K), which indicates the presence of a dynamic equilibrium between ion-molecular forms. According to the width of the absorption spectra, the bases in the region of 2.0 ≤ pH ≤ 8.0 can be arranged in the following row: MEA > Mf > KOH > DEA > TEA > MMEA. The bases can be arranged in the following rows for the effect on optical density at 490 nm: KOH > Mf ≥ MEA > DEA ≥ TEA (at 5.5 ≤ pH < 9.0); KOH = MEA = Mf > DEA = TEA (at pH < 6.0). According to the values of optical density at 360 nm in the region of 2.0 ≤ pH < 8.5, the bases can be arranged in the following row: Mf > KOH ≥ MEA ≥ DEA > MMEA > TEA. The total color difference (ΔE76) and specific color difference (SCD) values were calculated by colorimetric method as a function of pH. The acid–base dissociation constants in the SO2 – Am (KOH) – TrOOO – H2O systems significantly depend on the structure and physicochemical properties of the organic base and differ significantly from those in the HCl (HClO4, H2SO4) – MEA – TrOOO – H2O systems. The interrelation of colorimetric functions was established (total color difference and specific color difference) of SO2 – Am – TrOOO – H2O systems with molar refraction Am, empirical function pKa – lgPow, which combines the basicity and hydrophilicity of Am, formation constants of ammonium sulfites and hydrosulfites, pH- (dpH/dpQSO2), redox- (dЕ/dpQSO2) and conductometric (Dk) titration curves of Am aqueous solutions with gaseous sulfur dioxide.

Wide pH Range Potentiometric and Spectrophotometric Investigation into the Acidic Constants of Quercetin, Luteolin and l-Ascorbic Acid in Aqueous Media

It is now well established that the dissociation constants of an organic compound are characteristic of the types of groups, or the combinations of groups, contained in it. Furthermore, the acid–base dissociation constants are important parameters to fully understand the properties of a molecule in biological systems. In this framework, the aim of the present study was to determine the acidic constants of three natural molecules with well-known antioxidant properties, namely quercetin, luteolin and l-ascorbic acid. The evaluation was carried out in aqueous media (i.e., 0.16 M NaCl) at 37 °C in a wide pH range by using a combined approach based on potentiometric and spectrophotometric measurements. The results underline the necessity to employ both experimental techniques to obtain accurate values for acidic constants, preventing uncertainties related to undesirable oxidation reactions.

A new approach to the determination of pKa and pKb of Brønsted–Lowry weak acid and weak base in aprotic solvent

• Developing a method of determining the dissociation constants of weak acid and base in acetonitrile. • Unambiguous voltammetric peak potentials were used to exactly measure pK a and pK b . • Compared with using potentiometry, the method is simple and rapid because of using cyclic voltammetry. The pK a and pK b of Bronsted–Lowry weak acids and weak bases in aprotic solvents are difficult to accurately determine. Herein, we found that in an aprotic solvent, the conjugate base of weak acid can produce a new, unambiguous anodic peak of hydroquinone, and the conjugate acid of weak base can produce a new cathodic peak of p-benzoquinone. These new peaks were due to the drastic change in pH near the electrode surface, and their potentials depended on the strength of conjugate acids and bases but not on the concentration of hydroquinone and quinone. Therefore, the conjugate acid–base dissociation constant can be measured by the new peak potential. Then, the weak acid–base dissociation constant can be obtained by the difference between the autoprotolysis constant of the aprotic solvent and the conjugate acid–base dissociation constant. The experimental results were consistent with those in literature.

HOCH2CH2NH2 – TROPEOLIN OOO – H2O SYSTEM ACID-BASIC PROPERTIES IN THE PRESENCE OF HCl, HClO4, H2SO4 AND SO2H2O

The influence of hydrochloric, chloric, sulfuric and sulfurous acids (HCl, HClO4, H2SO4 and SO2×H2O, respectively) on protolytic equilibria in the system monoethanolamine (MEA) – tropeolin OOO (TrOOO) – water (CMEA = 0.1 M; pH = 1.0 ÷ 9.5) was studied by pH-metric, spectrophotometric and colorimetric methods. The acid-base behavior of the HOCH2CH2NH2 – TrOOO – H2O system was investigated at CTrOOO = 1,12 ×10-4 М, CMEA = 1,0×10-4 ÷ 1,0 М (pH = 8,25 ÷ 12,05), T = 293 K. TrOOO in this system exists in two tautomeric forms due to acid-base dissociation of the 4-OH group and associates formed by H-bonding with MEA molecules. There is a direct ratio between the pH values ​​of solutions and the total color difference (ΔE76), in contrast to the specific color difference (SCD). The difference in the behavior of the H2SO4 – HOCH2CH2NH2 – TrOOO – H2O system from the systems with HCl and HClO4 is due to the fact that the interaction of the first acid with MEA (8,0 £ pH) forms an ionic associate [HOCH2СH2NH3]2(SO4), which is more stable than ionic pairs [[HOCH2СH2NH3](HSO4), [HOCH2СH2NH3](ClO4), [HOCH2СH2NH3]Cl и [HOCH2СH2NH3](O3S-C­10H6-N=N-C6H4-SO3)[H3NCH2СH2OH]. Acid-base dissociation constants in systems significantly depend on the structure and physicochemical parameters of the mineral acid. In the electronic absorption spectra of the SO2 – MEA – TrOOO – H2O system (pH £ 7,5), there is a pronounced isobestic point at 415 nm, due to the dynamic equilibrium between ion-molecular forms. The coincidence of the maxima on the curves ΔE76 = f(pH) and SCD = f(pH) for the indicated system, in contrast to others studied in this work, was stated. The difference between the spectrophotometric and colorimetric behavior of the SO2 – MEA – TrOOO – H2O system from behavior of the systems with HCl, HClO4, and H2SO4 systems is due to the sulfur(IV)oxyanions with an azo indicator redox interaction.

BUFFER SOLUTIONS BASED ON TAURINE

The acid-base interaction in the aminoethanesulfonic acid (taurine, Tau) – potassium aminoethanesulfonate – water system was studied by pH-, redox- and conductometric methods in the temperature range 293–313 K. The ion-molecular composition of NH2CH2CH2SO3H –NH2CH2CH2SO3K – H2O system was calculated. It is shown aminoethanesulfonic acid in aqueous solutions to exist at the ratio CKOH/QTau < 0.5 mainly in the zwitterion form similar to systems with glycine, aminomethanesulfonic acid and its N‑alkylated derivatives. The content of the aminoethanesulfonate anion is directly proportional to the CKOH/QGly ratio. The studied system ionic strength and acid-base dissociation constant for the second stage of the aminoethanesulfonic acid concentration and temperature dependences were determined. The ionic strength values at the isoelectric point (mi.p.)are directly proportional to С0Tau and practically do not depend on the temperature within the error for the same series С0Tau and С0KOH .The pH limits of the buffer action are determined and the buffer capacity of these systems is estimated. It has been established that effective buffer zones of Tau aqueous solutions can to maintain acidity in the higher then physiological pH range at temperature range 293–313 K. The buffer capacity of NH2CH2CH2SO3H – NH2CH2CH2SO3K – H2O system exceeds the analogous values of YNHCH2SO3H – YNHCH2SO3K – H2O (Y = H, CH3, CH2CH2OH, C(CH3)3 and C2H5C6H5) systems. The obtained data on the buffer capacity of the aminoethanesulfonic acid – potassium aminoethanesulfonate – water system can be used in chemical analysis, microbiological and biochemical studies, and the acidity data of the solutions studied can simulate the chemisorption of acid gases (carbon and sulfur dioxides).

Synthesis, protolytic equilibria, and antimicrobial action of nifuroxazide analogs

The present paper reports on the synthesis of four hydrazones derived from 5-nitro-2-furfural, 5-nitro-2-thiophenal, isoniazid, 2,4- and 3,4-dihydroxy-N′-methylenebenzohydrazide. The acid-base dissociation constants of these compounds were determined in an aqueous solution. The protolytic equilibria-related ability of hydrazones to “sense” anions in dimethyl sulfoxide-containing water of different concentrations is studied using spectrophotometry, NMR spectroscopy, and quantum chemistry methods. The antimicrobial action of the hydrazones was tested and compared with that of the known drug nifuroxazide.

A New Approach to the Determination of pK <sub>a</sub> and pK <sub>b</sub> of Brønsted-Lowry Weak Acid and Weak Base in Aprotic Solvent

It is difficult to accurately determine the pKa and pKb of Bronsted-Lowry weak acids and weak bases in aprotic solvents. We found that in aprotic solvent, the conjugated base of weak acid can cause a new unambiguous anodic peak of hydroquinone, and the conjugated acid of weak base can cause a new cathodic peak of p-benzoquinone. The new peaks are due to the drastic change of pH near the electrode surface, and their potentials are dependent on the strength of conjugated acids and bases, but independent of the concentration of hydroquinone and quinone. Therefore, the conjugated acid-base dissociation constant can be measured by the new peak potential. Then the weak acid-base dissociation constant can be obtained by the difference between the autoprotolysis constant of the aprotic solvent and the conjugated acid-base dissociation constant. The experimental results are consistent with those in the literatures.

Electrochemical and spectroscopic characterization of biologically important Schiff bases

Redox behavior of two biologically important triazol derivatives i.e. (E)-1-((4H-1,2,4 triazol -4-ylimino) methyl)naphthalene-2-ol abbreviated as TMN and (E)-2-((4H-1,2,4 triazol -4-ylimino) methyl) 4-chlorophenol abbreviated as TMC was investigated on glassy carbon electrode surface. Experiments were carried over wide ranged concentration, pH, and temperature to evaluate various useful thermodynamic and kinetic parameters including ka, ΔG#, ΔH#, ΔS# along with Ea and diffusion co-efficient D. Thermodynamic data reveals that both compounds follow irreversible, pH dependent and diffusion-controlled oxidation processes which is both entropy and enthalpy opposed. Voltammetric studies help in determining the number of electrons and protons contributing in each oxidation reaction. The acid–base dissociation constant (pKa) value was found both by spectroscopic and electrochemical studies and the results obtained from both techniques were in good agreement. Computational studies give higher value of EHOMO, lower value of ELUMO, smaller orbital gap (ΔE) for TMN than TMB. Both the experimental and theoretical studies agree well in this regard and confirm that TMN is easily oxidizable compared to TMC. Sulforhodamine B assay demonstrated the non-cytotoxic character of the compounds up to 150 μM concentration. The present studies showed low cytotoxicity for these triazoles and their potential to be used as valuable compounds in biological applications.

Production and physicochemical characterization of a new amine derivative of gellan gum and rheological study of derived hydrogels

The production of an amine derivative of gellan gum, named GG-EDA, was here obtained by functionalizing the polysaccharide backbone with pendant ethylenediamine moieties. The obtained derivative was characterized by spectroscopic, colorimetric, chromatographic and rheological analyses to study the effect of the free amino groups on the physicochemical properties of the macromolecule. A titration experiment was conducted to study the acid-base dissociation constants in aqueous media for the carboxylic and amino groups in the GG-EDA and to shed light on the possibility that the derivative shows a polyampholyte structure under physiological conditions.The rheological analysis conducted on both physical and chemical hydrogels based on GG-EDA revealed that the presence of amino groups plays a fundamental role in influencing the viscoelastic properties and stability of the produced samples.

Three-way analysis of pH-UV absorbance dataset for the determination of paracetamol and its pKa value in presence of excipients.

A three-way analysis method, parallel factor analysis (PARAFAC) model was applied to the pH-absorbance dataset for the simultaneous determination of paracetamol and its acid-base dissociation constant in presence of excipient interference in a syrup formulation without using chemical pretreatment or chromatographic separation step. The UV spectroscopic data matrices of calibration set, validation and unknown samples were obtained from the absorbance measurements at the five different pH media, considering conjugate acid/base properties of the related drug. Their pH-absorbance data matrices were arranged as a cubic data array (wavelength x sample x pH) (425x52x5). Three-way array of pH-absorbance dataset was decomposed into a trilinear set of spectral, pH and relative concentration profiles of paracetamol and excipients in the commercial syrup using PARAFAC model. In the PARAFAC implementation, paracetamol in the commercial syrup formulation and its pKa value were simultaneously predicted from the relative concentration and pH profiles, respectively. In the method validation step of this study, the performance of PARAFAC model was checked by analyzing the validation samples in terms of selectivity, sensitivity, accuracy and precision of the method. The determination results of paracetamol and its pKa value provided from PARAFAC application were compared to those obtained by a newly developed ultra-performance liquid chromatography (UPLC) method, in terms of simplicity, applicability, interpretability with low cost and short analysis time.

Determination of thermodynamic acidity constants and limiting ionic mobilities of weak electrolytes by capillary electrophoresis using a new free software AnglerFish.

Thermodynamic acidity constants (acid or acid-base dissociation constants, sometimes called also as ionization constants) and limiting ionic mobilities (both of them at defined temperature, usually 25°C) are the fundamental physicochemical characteristics of a weak electrolyte, that is, weak acid or weak base or ampholyte. We introduce a novel method for determining the data of a weak electrolyte by the nonlinear regression of effective electrophoretic mobility versus buffer composition dependence when measured in a set of BGEs with various pH. To correct the experimental data for zero ionic strength we use the extended Debye-Hückel model and Onsager-Fuoss law with no simplifications. Contrary to contemporary approaches, the nonlinear regression is performed on limiting mobility data calculated by PeakMaster's correction engine, not on the raw experimental mobility data. Therefore, there is no requirement to perform all measurements at a constant ionic strength of the set of BGEs. We devised the computer program AnglerFish that performs the necessary calculations in a user-friendly fashion. All thermodynamic pKa values and limiting electrophoretic mobilities for arbitrarily charged substances having any number of ionic forms are calculated by one fit. The user input consists of the buffer composition of the set of BGEs and experimentally measured effective mobilities of the inspected weak electrolyte.

Prediction of pKa Using Machine Learning Methods with Rooted Topological Torsion Fingerprints: Application to Aliphatic Amines.

The acid-base dissociation constant, pKa, is a key parameter to define the ionization state of a compound and directly affects its biopharmaceutical profile. In this study, we developed a novel approach for pKa prediction using rooted topological torsion fingerprints in combination with five machine learning (ML) methods: random forest, partial least squares, extreme gradient boosting, lasso regression, and support vector regression. With a large and diverse set of 14 499 experimental pKa values, pKa models were developed for aliphatic amines. The models demonstrated consistently good prediction statistics and were able to generate accurate prospective predictions as validated with an external test set of 726 pKa values (RMSE 0.45, MAE 0.33, and R2 0.84 by the top model). The factors that may affect prediction accuracy and model applicability were carefully assessed. The results demonstrated that rooted topological torsion fingerprints coupled with ML methods provide a promising approach for developing accurate pKa prediction models.

Pt(hkl) surface charge and reactivity

Summary Interfacial charge has a decisive influence on the reactivity of the most common electrochemical reactions for practical applications. In this work, the concepts of surface charge and the different types of potential of zero charge are revised on model electrodes. The different methodologies for the determination of the potential of zero charge are reviewed. After that, a thorough examination of the effect of surface charge on different electrochemical reactions of interest is carried out. The acid–base dissociation constants on the surface or the kinetics of relevant electrocatalytic reactions such as nitrate and peroxodisulfate reduction, formic acid oxidation, oxygen and hydrogen peroxide reduction or hydrogen evolution is affected by the interfacial charge. Therefore, it is crucial to understand the surface charge characteristics of the electrode materials to obtain better electrocatalytic activity.