Estimation of the ionization p of pharmaceutical substances using the computer program

Hilal, S. H.; El-Shabrawy, Yasser; Carreira, L. A.; Karickhoff, Samuel W.; Toubar, Safaa S.; Rizk, M.

doi:10.1016/0039-9140(95)01789-5

Cited by 50 publications

(29 citation statements)

References 9 publications

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“…The average value of these LogP calculations was used for our analysis. The pK a values were calculated with the SPARC OnLine Calculator (http://archemcalc.com/sparc) (Hilal et al, 1996). Topological polar surface area (TPSA) was calculated by using the Interactive PSA calculator (http://www.molinspiration.com/services/ psa.html).…”

Section: Physicochemical Descriptorsmentioning

confidence: 99%

Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K

Astorga

Ekins

Morales

et al. 2012

J Pharmacol Exp Ther

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The present study compared the selectivity of two homologous transport proteins, multidrug and toxin extruders 1 and 2-K (MATE1 and MATE2-K), and developed three-dimensional pharmacophores for inhibitory ligand interaction with human MATE1 (hMATE1). The human orthologs of MATE1 and MATE2-K were stably expressed in Chinese hamster ovary cells, and transport function was determined by measuring uptake of the prototypic organic cation (OC) substrate 1-methyl-4-phenylpyridinium (MPP). Both MATEs had similar apparent affinities for MPP, with K tapp values of 4.4 and 3.7 M for MATE1 and MATE2-K, respectively. Selectivity was assessed for both transporters from IC 50 values for 59 structurally diverse compounds. Whereas the two transporters discriminated markedly between a few of the test compounds, the IC 50 values for MATE1 and MATE2-K were within a factor of 3 for most of them. For hMATE1 there was little or no correlation between IC 50 values and the individual molecular descriptors LogP, total polar surface area, or pK a . The IC 50 values were used to generate a common-features pharmacophore, quantitative pharmacophores for hMATE1, and a Bayesian model suggesting molecular features favoring and not favoring the interaction of ligands with hMATE1. The models identified hydrophobic regions, hydrogen bond donor and hydrogen bond acceptor sites, and an ionizable (cationic) feature as key determinants for ligand binding to MATE1. In summary, using a combined in vitro and computational approach, MATE1 and MATE2-K were found to have markedly overlapping selectivities for a broad range of cationic compounds, including representatives from seven novel drug classes of Food and Drug Administration-approved drugs.

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Section: Physicochemical Descriptorsmentioning

confidence: 99%

Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K

Astorga

Ekins

Morales

et al. 2012

J Pharmacol Exp Ther

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“…The SPARC program [32][33][34] allows not only estimation of the macroscopic pK a values but also the microscopic constants attributed to the different ionizable groups AD 10% pk AD = 9.46 ADB 7% pk ADB = 11.40 AEBD 29% pk AEBD = 13.37 pk DA = 7.69 AED 2% pk AED = 12.79 pk AEDB = 11.95 pk ADE = 11.86 ADBC 3% pk ADBC = 13.32 present in the compound. In fact, the macroscopic constants are predicted from the crossing of the charge curves of all the microspecies with the same charge.…”

Section: Estimation Of Pk a Values By The Computational Program Sparcmentioning

confidence: 99%

“…Correspondence: Dr. Clara Ràfols, Departament de Química Analítica, Universitat de Barcelona, Diagonal 647, E-08028 Barcelona, Spain E-mail: crafols@ub.edu Fax: In this work, we used CE for the pK a determination of flavonoids, some of them with low water solubility. The results have been compared with those obtained by a computational prediction program (SPARC) [32][33][34], which predicts both macroscopic and microscopic pK a values strictly from molecular structure using relatively simple reactivity models. It predicts also the preferential order of deprotonation of the different hydroxyl moieties in these compounds.…”

Section: General Aspectsmentioning

confidence: 99%

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Determination of dissociation constants of flavonoids by capillary electrophoresis

et al. 2005

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Ionization constants of some flavanols (catechin and epicatechin) and flavonols (kaempherol, fisetin, morin, and quercetin) are determined by capillary zone electrophoresis (CZE). This technique allows the determination of pK(a) values until about 12. The pK(a) values obtained are compared with those calculated by the SPARC computational program. This program predicts the microscopic and macroscopic pK(a) values and the order of deprotonation of the different -OH groups. While for catechin and epicatechin the first ionizable OH group occurs in ring 1 and the second ionizable group in ring 2, in flavonols the first deprotonation occurs in ring 2 and the second in ring 1.

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“…Nine commercially available or free programs for predicting ionization constants were compared [4]. Meloun et al [22] used the REGDIA regression diagnostics algorithm written in S-Plus [23] to critically examine the accuracy of pK a predictions with four programs (ACD/pK [24][25][26], Marvin [25,27], PALLAS [25,28] and SPARC [29,30]) considered the best. Balogh et al [25] found the most predictive and reliable predictors to be MARVIN and ACD/Percepta [26].…”

Section: Introductionmentioning

confidence: 99%

The Thermodynamic Overlapping pKa of the Antitumor Drug Ibrutinib Using Multiwavelength UV/VIS-Spectroscopy and Potentiometry

Meloun¹,

Mikešová²,

Pekárek³

et al. 2017

JAPLR

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Potentiometric and spectrophotometric pH-titrations of the antitumor drug Ibrutinib for dissociation constants determination were compared. Ibrutinib is targeting B-cell malignancies, for treatment of chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Chemometrics approach to the nonlinear regression of the pH-spectra (REACTLAB, SQUAD84) and pH-titration (ESAB) determines four dissociation constants. Ibrutinib exhibits four protonatable centers in a pH range of 2 to 10, where only two pK are well separated (ΔpK > 3), while the others are near dissociation constants of overlapping equilibria. The molecule LH 2 can protonate to sparingly soluble cations LH3+ and LH42+ and dissociate to anions LH -and L 2-. The set of spectra for pH from 2 to 11 in 220 to 300nm exhibits chromophore sensitivity to a pH change. Since pH above 10 and pH below 5 occurs in a titrated solution of a very fine precipitate of Ibrutinib, this part of the potentiometric titration curve pH over 10 and pH below 5 did not undergo regression analysis to estimate pK a´s . Depending on ionic strength the thermodynamic dissociation constants were estimated at 25°C and 37°C: pK a1 T = 3.22 and 3.22, pK a2 T = 4.17 and 5.21, pK a3 T = 6.77 and 6.77, pK a4 T = 9.82 and 9.81. Keywords:

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Estimation of the ionization p of pharmaceutical substances using the computer program

Cited by 50 publications

References 9 publications

Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K

Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K

Determination of dissociation constants of flavonoids by capillary electrophoresis

The Thermodynamic Overlapping pKa of the Antitumor Drug Ibrutinib Using Multiwavelength UV/VIS-Spectroscopy and Potentiometry

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