Aqueous pKa prediction for tautomerizable compounds using equilibrium bond lengths

Abstract

The accurate prediction of aqueous pK a values for tautomerizable compounds is a formidable task, even for the most established in silico tools. Empirical approaches often fall short due to a lack of pre-existing knowledge of dominant tautomeric forms. In a rigorous first-principles approach, calculations for low-energy tautomers must be performed in protonated and deprotonated forms, often both in gas and solvent phases, thus representing a significant computational task. Here we report an alternative approach, predicting pK a values for herbicide/therapeutic derivatives of 1,3-cyclohexanedione and 1,3-cyclopentanedione to within just 0.24 units. A model, using a single ab initio bond length from one protonation state, is as accurate as other more complex regression approaches using more input features, and outperforms the program Marvin. Our approach can be used for other tautomerizable species, to predict trends across congeneric series and to correct experimental pK a values.

Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

“…In contrast to the predicted values (6.54–7.70, calculated with the Chemicalize ChemAxon LLC software), the experimental p K a (H 2 O, 25 °C) of the bisbenzimidazole derivatives 2a – g was in the range 3.38–6.75 (i.e., % ionization at pH 7.4 ranging from 0.01 to 18.3), indicating that the compounds are mostly neutral at physiological pH (Table ). These measured p K a values were much lower (i.e., approximately 1.5–2 p K a units) than the predicted ones, highlighting the limits of p K a prediction tools for compounds containing a large number of possible tautomeric states. , In contrast, the bis­(2-aminoimidazolines) 1a – i are mostly dicationic, with experimental p K a values in the range 8.05–10.26 (i.e., > 85.5% ionized) that is approximately >1 p K a unit higher than the predicted ones. Replacement of the 2-aminoimidazoline heterocycles by pyridine-2-carboxamidine substituents led to a reduction of the p K a of the molecules by >2 p K a units, giving mean values in the range 4.19 ( 3h )–8.44 ( 19 ).…”

“…These measured pK a values were much lower (i.e., approximately 1.5−2 pK a units) than the predicted ones, highlighting the limits of pK a prediction tools for compounds containing a large number of possible tautomeric states. 53,54 In contrast, the bis(2-aminoimidazolines) 1a−i are mostly dicationic, with experimental pK a values in the range 8.05− 10.26 (i.e., > 85.5% ionized) that is approximately >1 pK a unit higher than the predicted ones. Replacement of the 2aminoimidazoline heterocycles by pyridine-2-carboxamidine substituents led to a reduction of the pK a of the molecules by >2 pK a units, giving mean values in the range 4.19 (3h)−8.44 (19).…”

A Dissipative Supramolecular Glue for Temporal Control of Amplified Enzyme Activity and Biocatalytic Cascades

“…The positively charged guanidinium headgroup was chosen to bind the triphosphate units of ATP through multivalent salt-bridge interactions (Figure 1b) 53 in a wide pH range owing to its high pKa value of 13.6. 54 The CnGua surfactant were synthesized following the protocol as described in the Supporting Information (SI) Figure S1 and characterized by 1 H-NMR, 13 C-NMR and mass spectrometry (Figure S2a-c). For the supramolecular system, we explored the ability of C16Gua to form transient assembled structures using ATP as a trivalent capping agent.…”

Easy to Use DFT Approach for Computational pKa Determination of Carboxylic Acids

“…Such model exploits the correlation between the equilibrium bond lengths at the reaction centre in the vacuum and the aqueous pKa, using B3LYP functional. [4][5][6] The pKa value of the target molecules can be extrapolate from a linear correlation fit. The methodology well describes the possibility to foresee compounds of pharmaceutical interest, as multi-protic molecules or tautomers.…”

“…To overcome this issue, the value of H + energy is arbitrary chosen from À 252.6 and À 271.7 kcal/mol À 1 , showing a gap ranging in up to 20 kcal/mol. [5] Conversely, with the direct approach, energy in gas phase and the H + values are not requested. [10] Moreover, it makes possible the addition from one to eight explicit water molecules, [11] to tune local interactions between solute and solvent molecules.…”