Prediction of toluene/water partition coefficients in the SAMPL9 blind challenge: assessment of machine learning and IEF-PCM/MST continuum solvation models.

In recent years the use of partition systems other than the widely used biphasic n-octanol/water has received increased attention to gain insight into the molecular features that dictate the lipophilicity of compounds. Thus, the difference between n-octanol/water and toluene/water partition coefficients has proven to be a valuable descriptor to study the propensity of molecules to form intramolecular hydrogen bonds and exhibit chameleon-like properties that modulate solubility and permeability. In this context, this study reports the experimental toluene/water partition coefficients (log Ptol/w) for a series of 16 drugs that were selected as an external test set in the framework of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) blind challenge. This external set has been used by the computational community to calibrate their methods in the current edition (SAMPL9) of this contest. Furthermore, the study also investigates the performance of two computational strategies for the prediction of log Ptol/w. The first relies on the development of two machine learning (ML) models, which are built up by combining the selection of 11 molecular descriptors in conjunction with either the multiple linear regression (MLR) or the random forest regression (RFR) model to target a dataset of 252 experimental log Ptol/w values. The second consists of the parametrization of the IEF-PCM/MST continuum solvation model from B3LYP/6-31G(d) calculations to predict the solvation free energies of 163 compounds in toluene and benzene. The performance of the ML and IEF-PCM/MST models has been calibrated against external test sets, including the compounds that define the SAMPL9 log Ptol/w challenge. The results are used to discuss the merits and weaknesses of the two computational approaches.

Insights into the Responding Modes of Highly Potent Gadolinium-Based Magnetic Resonance Imaging Probes Sensitive to Zinc Ions.

Zn ions (Zn2+) play an important biological role in many diseases; hence, an imaging method for monitoring the Zn2+ distribution in tissues could provide important clinical insights. Recently, we reported a potent Zn-sensitive probe based on the Gd-DO3A (DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylic acid), modified tyrosine. and di(2-picolyl)amine chelator for this metal cation, which generates an outstanding magnetic resonance imaging (MRI) response. Here we further explored the origin of this unprecedented response and expanded the choice of potential MRI probes by preparing the free acid version of the initial MRI sensor. We report a detailed investigation of the 1H NMR dispersion, 17O NMR, and isothermal titration calorimetry properties of these two MRI probes upon interaction with Zn2+. The performed experiments confirm selective interaction of the MRI probes and target metal cation, which causes substantial changes in the coordination sphere of the paramagnetic center. It also evidenced some aggregation, which enhances the relaxivity response. Interestingly, conversion of the methyl ester to the free carboxylic acid of the tyrosine moiety changes the nature of the aggregates and leads to a smaller relaxivity response. The probes interact with human serum albumin (HSA) in the absence of Zn2+, which leads to a possible modification of the coordination sphere of Gd3+ or a substantial change in the exchange rate of second-sphere water molecules. In the presence of Zn2+, the interaction with HSA is very weak, demonstrating the importance of the Zn2+ coordination sphere in the behavior of these systems.

Ionizable Drug Self-Associations and the Solubility Dependence on pH: Detection of Aggregates in Saturated Solutions Using Mass Spectrometry (ESI-Q-TOF-MS/MS).

It is widely accepted that solubility-pH profiles of ionizable compounds follow the Henderson-Hasselbalch equation. However, several studies point out that compounds often undergo additional processes in saturated solutions, such as sub-micellar oligomerization, micellar aggregation, or drug-buffer complexation among others, which make the experimental profiles deviate from the behavior predicted by the Henderson-Hasselbalch equation. Often, the presence of additional processes is supported by the analysis of experimental data through solubility computer programs. However, the purpose of this work is to experimentally prove the aggregation phenomena for a series of bases for which deviations from the theoretical profile have been observed. To this end, five monoprotic bases (lidocaine, maprotiline, cyproheptadine, bupivacaine, and mifepristone) susceptible to form ionic aggregates in solution have been selected, and mass spectrometry has been the technique of choice to prove the presence of aggregation. High declustering potentials have been applied to prevent aggregates from forming in the ionization source of the mass spectrometer. In addition, haloperidol has been used as a negative control since according to its profile, it is not suspected to form ionic aggregates. In all instances, except for haloperidol, the analysis of the saturated solutions revealed the presence of mixed-charged dimers (aggregates formed by a neutral molecule and a charged one) and even trimers in the case of mifepristone and bupivacaine. For lidocaine, the most soluble of the compounds, the presence of neutral aggregates was also detected. These experiments support the hypothesis that the simple Henderson-Hasselbalch equation may explain the solubility-pH behavior of certain compounds, but it can be somewhat inaccurate in describing the behavior of many other substances.

New Approach to Multivariate Standard Addition Based on Multivariate Curve Resolution by Alternating Least-Squares: Application to Voltammetric Data.

A multivariate version of the classical univariate standard addition method is proposed for the analysis of samples generating overlapping signals in the presence of notorious matrix effects. Unlike previous versions based on multivariate calibration by partial least-squares (PLS), the proposed strategy takes advantage of a self-modeling methodology: multivariate curve resolution by alternating least-squares (MCR-ALS) enhanced with signal shape constraints based on parametric functions. In this way, there is no need for the full multivariate response of a blank solution, and in multianalyte determinations, the standard additions can be made with a solution containing all of the analytes, which constitutes a clear advance as compared to PLS approach. The proposed method has been successfully tested in the voltammetric determination of hydroquinone and catechol in solutions of increasing complexity and appears to be a promising tool in the field of electroanalysis.

Prediction of the n-octanol/water partition coefficients in the SAMPL6 blind challenge from MST continuum solvation calculations.

The IEFPCM/MST continuum solvation model is used for the blind prediction of n-octanol/water partition of a set of 11 fragment-like small molecules within the SAMPL6 Part II Partition Coefficient Challenge. The partition coefficient of the neutral species (log P) was determined using an extended parametrization of the B3LYP/6-31G(d) version of the Miertus-Scrocco-Tomasi continuum solvation model in n-octanol. Comparison with the experimental data provided for partition coefficients yielded a root-mean square error (rmse) of 0.78 (log P units), which agrees with the accuracy reported for our method (rmse = 0.80) for nitrogen-containing heterocyclic compounds. Out of the 91 sets of log P values submitted by the participants, our submission is within those with an rmse < 1 and among the four best ranked physical methods. The largest errors involve three compounds: two with the largest positive deviations (SM13 and SM08), and one with the largest negative deviations (SM15). Here we report the potentiometric determination of the log P for SM13, leading to a value of 3.62 ± 0.02, which is in better agreement with most empirical predictions than the experimental value reported in SAMPL6. In addition, further inclusion of several conformations for SM08 significantly improved our results. Inclusion of these refinements led to an overall error of 0.51 (log P units), which supports the reliability of the IEFPCM/MST model for predicting the partitioning of neutral compounds.

Electroanalysis from the past to the twenty-first century: challenges and perspectives.

A personal mini-review is presented on the history of electroanalysis and on their present achievements and future challenges. The manuscript is written from the subjective view of two generations of electroanalytical chemists that have witnessed for many years the evolution of this discipline.

Why Not Glycine Electrochemical Biosensors?

Glycine monitoring is gaining importance as a biomarker in clinical analysis due to its involvement in multiple physiological functions, which results in glycine being one of the most analyzed biomolecules for diagnostics. This growing demand requires faster and more reliable, while affordable, analytical methods that can replace the current gold standard for glycine detection, which is based on sample extraction with subsequent use of liquid chromatography or fluorometric kits for its quantification in centralized laboratories. This work discusses electrochemical sensors and biosensors as an alternative option, focusing on their potential application for glycine determination in blood, urine, and cerebrospinal fluid, the three most widely used matrices for glycine analysis with clinical meaning. For electrochemical sensors, voltammetry/amperometry is the preferred readout (10 of the 13 papers collected in this review) and metal-based redox mediator modification is the predominant approach for electrode fabrication (11 of the 13 papers). However, none of the reported electrochemical sensors fulfill the requirements for direct analysis of biological fluids, most of them lacking appropriate selectivity, linear range of response, and/or capability of measuring at physiological conditions. Enhanced selectivity has been recently reported using biosensors (with an enzyme element in the electrode design), although this is still a very incipient approach. Currently, despite the benefits of electrochemistry, only optical biosensors have been successfully reported for glycine detection and, from all the inspected works, it is clear that bioengineering efforts will play a key role in the embellishment of selectivity and storage stability of the sensing element in the sensor.

Voltammetric Electronic Tongues in Food Analysis.

A critical revision is made on recent applications of voltammetric electronic tongues in the field of food analysis. Relevant works are discussed dealing with the discrimination of food samples of different type, origin, age and quality and with the prediction of the concentration of key substances and significant indexes related to food quality.

Ag Nanoparticles Drop-Casting Modification of Screen-Printed Electrodes for the Simultaneous Voltammetric Determination of Cu(II) and Pb(II).

A new silver nanoparticle modified screen-printed electrode was developed and applied to the simultaneous determination of Pb(II) and Cu(II). Two different types of silver nanoparticles with different shapes and sizes, Ag nanoseeds and Ag nanoprisms, were microscopically characterized and three different carbon substrates, graphite, graphene and carbon nanofibers, were tested. The best analytical performance was achieved for the combination of Ag nanoseeds with a carbon nanofiber modified screen-printed electrode. The resulting sensor allowed the simultaneous determination of Pb(II) and Cu(II) at trace levels and its applicability to natural samples was successfully tested with a groundwater certified reference material, presenting high reproducibility and trueness.

Binding thermodynamics of paromomycin, neomycin, neomycin-dinucleotide and -diPNA conjugates to bacterial and human rRNA.

Isothermal titration calorimetry (ITC) is a powerful technique able to evaluate the energetics of target-drug binding within the context of drug discovery. In this work, the interactions of RNAs reproducing bacterial and human ribosomal A-site, with two well-known antibiotic aminoglycosides, Paromomycin and Neomycin, as well as several Neomycin-dinucleotide and -diPNA conjugates, have been evaluated by ITC and the corresponding thermodynamic quantities determined. The comparison of the thermodynamic data of aminoglycosides and their chemical analogues allowed to select Neomycin-diPNA conjugates as the best candidates for antimicrobial activity.

Molecular details of INH-C10 binding to wt KatG and Its S315T mutant.

Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C10 appears to be a very promising lead compound for drug development.

Application of HPLC-UV combined with chemometrics for the detection and quantification of 'true cinnamon' adulteration.

Cinnamon is one of the most popular spices used in cuisines worldwide. Among its different species, Ceylon cinnamon ("true cinnamon") is the one with the most health benefits due to its high concentration in the antioxidant eugenol and the ultra-low content of the hepatotoxic compound coumarin. However, the higher price of Ceylon cinnamon makes it vulnerable to fraudulent adulteration with more economic species of cinnamon, such as Cassia and Saigon. Thus, for the detection of frauds in cinnamon samples, a HPLC-UV method was developed for the determination of 4 characteristic cinnamon compounds: eugenol, cinnamaldehyde, coumarin and cinnamic acid. The obtained data were analyzed by PLS to attain not only the authentication of cinnamon species but also the detection and quantification of partial adulterations. Several mixtures prepared in the laboratory using different cinnamon powder samples considered 'pure' Ceylon, Cassia or Saigon were tested, concluding that the proposed approach allows a clear identification of Ceylon cinnamon and a suitable quantification of the Ceylon: non-Ceylon ratio regardless of the commercial sample selected (RMSE <0.06 for both training and test sets).

Temperature variation effects on the determination of acidity constants through the internal standard-capillary electrophoresis method.

The internal standard (IS) CE (IS-CE) method is an interesting alternative to other methods for the determination of acidity constants of compounds. Although some of the advantages of this method have been already reported, the method has not been tested yet as regards to temperature effects. This has been the aim of this work, where it is demonstrated that the method can be applied successfully for the determination of pK(a) s at different temperatures, if the acidity constant of the IS at the desired temperature is known. The fact of obtaining the acidity constants at different temperatures allows the calculation of some thermodynamic quantities, such as the molar standard enthalpy and the molar standard entropy in a fast way. It is also demonstrated that if the IS and the test compound have similar standard enthalpy increment, the IS compensates uncontrolled possible temperature fluctuations (e.g., due to Joule heat) inside the capillary obtaining reliable acidity constant values at the desired temperature.

Modeling nonspecific toxicity of organic compounds to the fathead minnow fish by means of chromatographic systems.

The performance of chromatographic systems to mimic aquatic toxicity to the fathead minnow fish is evaluated taking into account the factors that contribute to the variance of biological-chromatographic correlations. These factors are the precision to measure the fathead minnow toxicity, the precision of the surrogate chromatographic system, and the error from the dissimilarity between the fathead minnow and chromatographic systems. The precisions are estimated through the characterization of the systems by the solvation parameter model. Several chromatographic systems as well as the common reference octanol-water partition system have been selected to test their ability to model the nonspecific toxicity to the fathead minnow by means of the proposed approach. Predictions and experimental tests show that the micellar electrokinetic chromatography system of sodium taurocholate and chromatographic measurements using an immobilized artificial membrane column provide the most precise estimations of this biopartitioning property. The octanol-water partition system, the conventional C18 high-performance liquid chromatography systems, and the micellar electrokinetic chromatography system of sodium dodecylsulfate show worse performances.

Molecular characteristics of several drugs evaluated from solvent/water partition measurements: Solvation parameters and intramolecular hydrogen bond indicator.

A wide set of well-known drugs, most of them included in the Abraham´s reference database, covering a wide variety of chemical structures and therapeutical functionalities were chosen in order to determine some molecular properties from solvent/water partition measurements. Partition data from aqueous solutions and four different solvents (n-dodecane, toluene, chloroform and n-octanol) were measured and reported. From them, Abraham´s molecular descriptors of selected compounds (A, B and S, accounting for hydrogen bond donor, hydrogen bond acceptor and dipolarity/polaritzability, respectively) were estimated. A and B values derived from the experimental measurements strongly agree with the tabulated ones showing the suitability of the used procedure to achieve reliable values for new molecules. However, obtained S values differ from those previously reported for several compounds. Moreover, values for a new indicator of the propensity to form intramolecular hydrogen bonds (Δlog Poct-tol) were estimated from the experimental data and also calculated according to both, the Abraham´s model and the molecular structures (SMD). The quality of both series of calculated descriptors was evaluated by contrast with the experimental values and satisfactory results were obtained in both instances. Thus, the Abraham´s way is useful when molecular descriptors are available but very good estimations can be achieved by SMD, which only requires the drug´s molecular structure.

A hybrid sensing system combining simultaneous optical and electrochemical measurements: Application to beer discrimination.

A hybrid sensing system, which combines simultaneous cyclic voltammetric (CV) and UV-vis absorbance measurements using a commercial carbon screen-printed electrode and a set of optical fibres in disposable cuvettes, is proposed. The hybrid system approach was applied to 27 samples of recognized beer brands, improving the classification power as compared to only voltammetric or only spectrophotometric measurements. The developed partial least squares discriminant analysis (PLS-DA) model was able to discriminate between five types of beer (lager, marzen, black/stout, alcohol-free and white/ale). The model was also successfully applied to 28 beer samples of white-label brands sold in local supermarkets, demonstrating their similarity to recognized brand beers.

Virtual Cocrystal Screening of Adefovir Dipivoxyl: Identification of New Solid Forms with Improved Dissolution and Permeation Profiles.

The application of a computational screening methodology based on the calculation of intermolecular interaction energies has guided the discovery of new multicomponent solid forms of the oral antiviral Adefovir Dipivoxyl. Three new cocrystals with resorcinol, orcinol and hydroquinone have been synthesized and thoroughly characterized. They show improved dissolution profiles with respect to the single solid form, particularly the cocrystals of orcinol and resorcinol, which have 3.2- and 2-fold faster dissolution rates at stomach conditions (pH 1.5). Moreover, dynamic dissolution experiments that simultaneously mimic both the pH variation along the gastrointestinal tract and the partition into biological membranes show that, in addition to the faster initial dissolution, Adefovir Dipivoxyl also penetrates faster into the organic membranes in the form of resorcinol and orcinol cocrystals.

Enhanced voltammetric performance of sensors based on oxidized 2D layered black phosphorus.

The exceptional properties of 2D layered black phosphorus (BP) make it a promising candidate for electrochemical sensing applications and, even though BP is considered unstable and tends to degrade by the presence of oxygen and moisture, its oxidation can be beneficial in some situations. In this work, we present an unequivocal demonstration that the exposition of BP-based working electrodes to normal ambient conditions can indeed be advantageous, leading to an enhancement of voltammetric sensing applications. This point was proved using a BP modified screen-printed carbon electrode (BP-SPCE) for the voltammetric determination of dopamine (DA) as a model target analyte. Oxidized BP-SPCE (up to 35% of PxOy at the surface) presented an enhanced analytical performance with a 5-fold and 2-fold increase in sensitivity, as compared to bare-SPCE and non-oxidized BP-SPCE stored in anhydrous atmosphere, respectively. Good detection limit, repeatability, reproducibility, stability, selectivity, and accuracy were also achieved. Overall, the results presented herein display the prominent possibilities of preparing and working with BP based-sensors in normal ambient settings and showcase their implementation under physiological conditions.

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile.

A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values.

Evaluation of the Interactions between Human Serum Albumin (HSA) and Non-Steroidal Anti-Inflammatory (NSAIDs) Drugs by Multiwavelength Molecular Fluorescence, Structural and Computational Analysis.

The interaction between drugs and transport proteins, such as albumins, is a key factor in drug bioavailability. One of the techniques commonly used for the evaluation of the drug-protein complex formation is fluorescence. This work studies the interaction of human serum albumin (HSA) with four non-steroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, naproxen, and diflunisal-by monitoring the fluorescence quenching when the drug-albumin complex is formed. Two approaches-the double logarithm Stern-Volmer equation and the STAR program-are used to evaluate the binding parameters. The results are analyzed considering the binding properties, determined by using other complementary techniques and the available structural information of albumin complexes with NSAID-related compounds. Finally, this combined analysis has been synergistically used to interpret the binding of flurbiprofen to HSA.