Reliable and accurate prediction of basic pKa values in nitrogen compounds: The pKa shift in supramolecular systems as a case study
Author:
Alcázar Jackson J.1, Saide Alessandra C. Misad, Campodónico Paola R.1
Affiliation:
1. Universidad del Desarrollo
Abstract
Abstract
This article presents a Quantitative Structure-Activity Relationship (QSAR) approach for predicting the acid dissociation constant (pK \(_a\) ) of nitrogenous compounds, including those within supramolecular complexes based on cucurbiturils. The model combines low-cost quantum mechanical calculations with QSAR methodology and linear regressions to achieve accurate predictions for a broad range of nitrogen-containing compounds. The model was developed using a diverse dataset of 130 nitrogenous compounds and exhibits excellent predictive performance, with a high coefficient of determination (R \(^2\) ) of 0.9905, low standard error (s) of 0.3066, and high Fisher statistic (F) of 2142. The model outperforms existing methods, such as Chemaxon software and previous studies, in terms of accuracy and its ability to handle heterogeneous datasets. External validation on pharmaceutical ingredients, dyes, and supramolecular complexes based on cucurbiturils confirms the reliability of the model. To enhance usability, a script-like tool has been developed, providing a streamlined process for users to access the model. This study represents a significant advancement in pK$_a$ prediction, offering valuable insights for drug design and supramolecular system optimization.
Publisher
Research Square Platform LLC
Reference118 articles.
1. Assaf, Khaleel I. and Nau, Werner M. (2015) {Cucurbiturils: From synthesis to high-affinity binding and catalysis}. Chemical Society Reviews 44(2): 394--418 https://doi.org/10.1039/c4cs00273c, http://xlink.rsc.org/?DOI=C4CS00273C, Royal Society of Chemistry, dec, 14604744, :C\:/Users/Usuario/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Assaf, Nau - 2015 - Cucurbiturils from synthesis to high-affinity binding and catalysis.pdf:pdf, In the wide area of supramolecular chemistry, cucurbit[n]urils (CBn) present themselves as a young family of molecular containers, able to form stable complexes with various guests, including drug molecules, amino acids and peptides, saccharides, dyes, hydrocarbons, perfluorinated hydrocarbons, and even high molecular weight guests such as proteins (e.g., human insulin). Since the discovery of the first CBn, CB6, the field has seen tremendous growth with respect to the synthesis of new homologues and derivatives, the discovery of record binding affinities of guest molecules in their hydrophobic cavity, and associated applications ranging from sensing to drug delivery. In this review, we discuss in detail the fundamental properties of CBn homologues and their cyclic derivatives with a focus on their synthesis and their applications in catalysis. 2. Alc{\'{a}}zar, Jackson J. and M{\'{a}}rquez, Edgar and Garc{\'{i}}a-R{\'{i}}o, Luis and Robles-Mu{\ {n}}oz, Agust{\'{i}}n and Fierro, Ang{\'{e}}lica and Santos, Jos{\'{e}} G. and Aliaga, Margarita E. (2022) {Changes in Protonation Sites of 3-Styryl Derivatives of 7-(dialkylamino)-aza-coumarin Dyes Induced by Cucurbit[7]uril}. Frontiers in Chemistry 10: 273 https://doi.org/10.3389/fchem.2022.870137, https://www.frontiersin.org/articles/10.3389/fchem.2022.870137/full, Frontiers, 35494653, apr, 7-dialkylamino-aza-coumarin dyes,Heterocyclic nitrogen protonation,Protonation induced by cucurbit[7]uril,molecular recognition by cucurbit[7]uril,spectral behaviour of protomers, 2296-2646, The incorporation of a guest, with different basic sites, into an organized system (host), such as macrocycles, could stabilize, detect, or promote the formation of a certain protomer. In this context, this work aimed to study the influence of cucurbit[7]uril (CB7) on dyes such as 7-(dimethylamino)-aza-coumarins, which have more than one basic site along their molecular structure. For this, three 3-styryl derivatives of 7-(dialkylamino)-aza-coumarin dyes ( SAC1-3 ) were synthesized and characterized by NMR, ESI-HRMS and IR. The spectral behaviour of the SACs in the absence and presence of CB7 was studied. The results showed large shifts in the UV-vis spectrum in acid medium: a hypsochromic shift of ≈5400 cm −1 ( SAC1-2 ) and ≈3500 cm −1 ( SAC3 ) in the absence of CB7 and a bathochromic shift of ≈4500 cm −1 ( SAC1-3 ) in the presence of CB7. The new absorptions at long and short wavelengths were assigned to the corresponding protomers by computational calculations at the density functional theory (DFT) level. Additionally, the binding mode was corroborated by molecular dynamics simulations. Findings revealed that in the presence of CB7 the heterocyclic nitrogen was preferably protonated instead of the dialkylamino group. Namely, CB7 induces a change in the protonation preference at the basic sites of the SACs, as consequence of the molecular recognition by the macrocycle. 3. Silakari, Om and Singh, Pankaj Kumar (2021) {ADMET tools: Prediction and assessment of chemical ADMET properties of NCEs}. Concepts and Experimental Protocols of Modelling and Informatics in Drug Design : 299--320 https://doi.org/10.1016/b978-0-12-820546-4.00014-3, Academic Press, jan, 978-0-12-820546-4, Investigation of reasons for increased costs in the new drug discovery and development revealed poor pharmacokinetic (Absorption, Distribution, Metabolism, Discretion) and Toxicity properties as the primary cause of drug failure in the development phase rather than unsatisfactory efficacy. The high attrition rate of drug candidates in development, has led to a new strategy to introduce early, parallel evaluation of efficacy and biopharmaceutical properties of drug candidates. Additionally, different strategies to accelerate lead finding and lead optimization processes has shifted the chemical libraries towards poorer biopharmaceutical properties. Thus, high throughput and fast ADMET profiling tools and techniques is very important as it allows prioritization of leads or drug candidates by their biopharmaceutical properties in parallel with optimization of their efficacy at early discovery phases. This is expected to improve the overall quality of drug candidates and the probability of their success. In this chapter, ADME profiling in relation to the drug discovery and development process is discussed. 4. Seybold, Paul G. and Kreye, W. C. (2012) {Theoretical estimation of the acidities of alcohols and azoles in gas phase, DMSO, and water}. International Journal of Quantum Chemistry 112(24): 3769--3776 https://doi.org/10.1002/qua.24216, https://onlinelibrary.wiley.com/doi/full/10.1002/qua.24216, John Wiley & Sons, Ltd, dec, DMSO,acidity,alcohols,azoles,gas phase,pK a, 00207608, :C\:/Users/Usuario/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Seybold, Kreye - 2012 - Theoretical estimation of the acidities of alcohols and azoles in gas phase, DMSO, and water.pdf:pdf, Most acidities and basicities of chemical compounds are measured in aqueous solution since this solvent is most important for biochemical and environmental applications, but the acidities of compounds in the gas phase and in other solvents can also be of interest. As a polar, aprotic solvent, dimethyl sulfoxide (DMSO) presents a unique environment for acid dissociation, and this solvent offers informative comparisons with both the vacuum and aqueous environments. Here, quantum chemical approaches previously used for the estimation of aqueous pK a values are applied to the estimation of DMSO, aqueous, and gas-phase acidities for two representative series of compounds: alcohols/phenols and azoles. Calculations were performed using both the semiempirical RM1 method and density functional theory (B3LYP/6-31 +G*) . The effectiveness of the SM5.4 and SM8 solvent models in estimating the solution-phase acidities was also examined. {\textcopyright} 2012 Wiley Periodicals, Inc. 5. R{\`{a}}fols, Clara and Bosch, Elisabeth and Ruiz, Rebeca and Box, Karl J. and Reis, Marina and Ventura, Cristina and Santos, Susana and Ara{\'{u}}jo, M. Eduarda and Martins, Filomena (2012) {Acidity and hydrophobicity of several new potential antitubercular drugs: Isoniazid and benzimidazole derivatives}. Journal of Chemical and Engineering Data 57(2): 330--338 https://doi.org/10.1021/je200827u, https://pubs.acs.org/doi/full/10.1021/je200827u, American Chemical Society, feb, 00219568, :C\:/Users/Usuario/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/R{\`{a}}fols et al. - 2012 - Acidity and hydrophobicity of several new potential antitubercular drugs Isoniazid and benzimidazole derivatives.pdf:pdf, Hydrophobicity values (log P o/w) determined both by potentiometry and by the conventional shake-flask method and aqueous pK a values obtained by potentiometry for seven isoniazid and nine benzimidazole derivatives are presented. Several of these compounds have strong hydrophilic or hydrophobic character, and some of them show two or more ionizable sites, sometimes very acidic or very basic. These facts have compelled us to work near the limits of the potentiometric technique, and therefore, a critical evaluation of the results obtained in these extreme working conditions is presented. Particularly, details about the potentiometric determination of log P o/w values of the most hydrophilic and most hydrophobic compounds are clearly described. {\textcopyright} 2011 American Chemical Society.
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