Estimation of microscopic, zwitterionic ionization constants, isoelectric point and molecular speciation of organic compounds

Hilal, S. H.; Karickhoff, Samuel W.; Carreira, L. A.

doi:10.1016/s0039-9140(99)00157-5

Cited by 29 publications

(28 citation statements)

References 4 publications

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“…The hydroxyl p K a values (Table 1) of the studied antimycins were estimated by the SPARC method, 50 which seems to take the intramolecular H-bond into account. The magnitude of the p K a values (range 4.6–8.0) is determined mainly by the electron-withdrawing ability of the R 1 substituents on the phenol ring, with the R 2 substituents exhibiting a slighter influence.…”

Section: Resultsmentioning

confidence: 99%

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Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins

Natesan

Wang²,

Lukáčová³

et al. 2012

J. Med. Chem.

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We present the cellular quantitative structure–activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug’s lipophilicity, acidity, and other properties. We conceptually combined the DF with our multispecies, multimode version of the frequently used ligand-based comparative molecular field analysis (CoMFA) method, forming a single correlation function for fitting the cell-level activities. The resulting cell-QSAR model was applied to the Selwood data on filaricidal activities of antimycin analogues. Their molecules are flexible, ionize under physiologic conditions, form different intramolecular H-bonds for neutral and ionized species, and cross several membranes to reach unknown receptors. The calibrated cell-QSAR model is significantly more predictive than other models lacking the disposition part and provides valuable structure optimization clues by factorizing the cell-level activity of each compound into the contributions of the receptor binding and disposition.

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Section: Resultsmentioning

confidence: 99%

“…Our multispecies approach can take into account tautomers and hydrates of aldehydes and ketones; hence, formation of these species was examined using the SPARC Web server 50 and was found negligible for all compounds on the basis of the following reasoning.…”

Section: Methodsmentioning

confidence: 99%

Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins

Natesan

Wang²,

Lukáčová³

et al. 2012

J. Med. Chem.

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“…Subsequently, ionization estimates were performed only for tautomer having the fraction of at least 0.01% to determine the fraction of individual species as a function of pH. In both cases, the SPARC web server 36 was used.…”

Section: Methodsmentioning

confidence: 99%

Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

et al. 2012

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Treatment of ionization and tautomerism of ligands and receptors is one of the unresolved issues in structure-based prediction of binding affinities. Our solution utilizes the thermodynamic master equation, expressing the experimentally observed association constant as the sum of products, each valid for a specific ligand–receptor species pair, consisting of the association microconstant and the fractions of the involved ligand and receptor species. The microconstants are characterized by structure-based simulations, which are run for individual species pairs. Here we incorporated the multispecies approach into the QM/MM linear response method and used it for structural correlation of published inhibition data on mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) by 66 benzothiophene and pyrrolopyridine analogues, forming up to five tautomers and seven ionization species under experimental conditions. Extensive cross-validation showed that the resulting models were stable and predictive. Inclusion of all tautomers and ionization ligand species was essential: the explained variance increased to 90% from 66% for the single-species model.

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“…1). pKa value gives information about the tendency for an acid to lose a proton to a solvent or the affinity of a base to accept a proton and is an expression of acid-base properties of a substance in solution [38]. Knowledge of pKa values is important for the quantitative treatment of systems involving acid-base equilibria in solution and also it is a very important physicochemical property in medicinal chemistry which can be used to predict distribution, metabolism, excretion and biological activity of a chemical/drug [39].…”

Section: Determination Of Pka and Purity Ofmentioning

confidence: 99%

Synthesis, Characterization and Cytotoxicity Evaluation of an Oleic Acid Derived Novel Bicephalous Dianionic Surfactant

Kalhapure

Akamanchi

2015

J Surfact & Detergents

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A novel oleic acid derived bicephalous dianionic surfactant disodium (Z) 3,3 0 -(oleoylazanediyl)dipropanoate containing one hydrophobic carbon chain and two hydrophilic head groups was synthesized, characterized and evaluated for cytotoxicity for the purpose of introducing a new biocompatible surfactant. The head group 3,3 0 -azanediyldipropanoate was synthesized through Michael addition of methyl acrylate to benzylamine and subsequent reductive debenzylation with Pd/C, H 2 and was condensed with an oleic acid moiety via amide bond formation. Ester groups at the periphery were hydrolyzed using acetyl chloride-water and the diacid formed was neutralized with sodium bicarbonate to obtain the desired surfactant. The CMC was determined by conductometry, log P octanol/water by ChemSW software and the hydrophiliclipophilic balance (HLB) by the Davies method and ChemSW. In vitro cytotoxicity study was performed using sulforhodamine B assay and the in vivo skin irritation study was performed on male New Zealand white rabbits as per OECD guideline 404. The CMC was found to be 1.9 mm/l which was almost half of the CMC of sodium oleate. The Log P octanol/water value of -3.87 and the HLB values of 35.22 and 34.46 by the Davies method and ChemSW software respectively revealed the hydrophilic nature of the surfactant. The surfactant did not exhibit any cytotoxicity at any of the concentrations tested and was found to be non-irritating by in vivo skin irritation studies. The findings of the present work suggest that the synthesized novel bicephalous dianionic surfactant is a safe and biocompatible excipient. It has the potential to be an attractive alternative to linear and gemini surfactants for applications in biological studies and pharmaceutical drug delivery systems.

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Estimation of microscopic, zwitterionic ionization constants, isoelectric point and molecular speciation of organic compounds

Cited by 29 publications

References 4 publications

Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins

Cellular Quantitative Structure–Activity Relationship (Cell-QSAR): Conceptual Dissection of Receptor Binding and Intracellular Disposition in Antifilarial Activities of Selwood Antimycins

Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

Synthesis, Characterization and Cytotoxicity Evaluation of an Oleic Acid Derived Novel Bicephalous Dianionic Surfactant

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