Aqueous Solubility Of Compounds Research Articles

Prediction of organic compound aqueous solubility using machine learning: a comparison study of descriptor-based and fingerprints-based models

A reliable and practical determination of a chemical species’ solubility in water continues to be examined using empirical observations and exhaustive experimental studies alone. Predictions of chemical solubility in water using data-driven algorithms can allow us to create a rationally designed, efficient, and cost-effective tool for next-generation materials and chemical formulations. We present results from two machine learning (ML) modeling studies to adequately predict various species’ solubility using data for over 8400 compounds. Molecular-descriptors, the most used method in previous studies, and Morgan fingerprint, a circular-based hash of the molecules' structures, were applied to produce water solubility estimates. We trained all models on 80% of the total datasets using the Random Forest (RFs) technique as the regressor and tested the prediction performance using the remaining 20%, resulting in coefficient of determination (R2) test values of 0.88 and 0.81 and root-mean-square deviation (RMSE) test values 0.64 and 0.80 for the descriptors and circular fingerprint methods, respectively. We interpreted the produced ML models and reported the most effective features for aqueous solubility measures using the Shapley Additive exPlanations (SHAP) and thermodynamic analysis. Low error, ability to investigate the molecular-level interactions, and compatibility with thermodynamic quantities made the fingerprint method a distinct model compared to other available computational tools. However, it is worth emphasizing that physicochemical descriptor model outperformed the fingerprint model in achieving better predictive accuracy for the given test set.

AqSolDB, a curated reference set of aqueous solubility and 2D descriptors for a diverse set of compounds

Water is a ubiquitous solvent in chemistry and life. It is therefore no surprise that the aqueous solubility of compounds has a key role in various domains, including but not limited to drug discovery, paint, coating, and battery materials design. Measurement and prediction of aqueous solubility is a complex and prevailing challenge in chemistry. For the latter, different data-driven prediction models have recently been developed to augment the physics-based modeling approaches. To construct accurate data-driven estimation models, it is essential that the underlying experimental calibration data used by these models is of high fidelity and quality. Existing solubility datasets show variance in the chemical space of compounds covered, measurement methods, experimental conditions, but also in the non-standard representations, size, and accessibility of data. To address this problem, we generated a new database of compounds, AqSolDB, by merging a total of nine different aqueous solubility datasets, curating the merged data, standardizing and validating the compound representation formats, marking with reliability labels, and providing 2D descriptors of compounds as a Supplementary Resource.

Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents.

Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with MIC values ≤0.5 μg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif(R) and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy.

Identifying the Correct Biotransformation Model from Polychlorinated Biphenyl and Dioxin Dechlorination Batch Studies.

We performed Monte Carlo simulations of batch transformations of hydrophobic compounds using typical numbers of data points, extent of reaction, and measurement error, to identify the most appropriate biotransformation model to describe such data under different conditions. Highly hydrophobic compounds such as polychlorinated biphenyls (PCBs) and dioxins present special challenges for parameterization due to low environmental concentrations and slow biotransformation rates, which result in high sample variability, few samples, and limited substrate concentration range. Four models of varying complexity (zero-order, first-order, Monod, and Best) were fit to simulated data. Various combinations of initial concentration (S0), half saturation concentration (KS), maximum substrate utilization rate (qmax), measurement error, number of data points per batch run, and extent of biotransformation were simulated. One thousand Monte-Carlo runs were performed for each parameter combination, and AICc (Akaike's information criterion corrected for small numbers of data points) was used to determine the most appropriate model. Neither the Best model nor the zero-order model ever produced the lowest AICc for a majority of simulations under any combination of test conditions. With 10% measurement error, the first-order model always outperformed the others. In the case of 1% measurement error with 10 evenly-spaced data points, the Monod model was the better choice when S0>KS and the system was not mass transfer limited [Formula: see text] otherwise, the first-order model was indicated. S0 is constrained by the compound's aqueous solubility; therefore, for highly hydrophobic compounds such as PCBs or polychlorinated dibenzo-p-dioxins and dibenzofurans, a first-order model is likely to fit batch biotransformation data as well or better than a more complicated model.

Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups?

Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3-triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.

Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in Beagle Dogs

Potency and activity of SR13668 in cancer prevention have been proven in several in vitro and in vivo cancer models. However, the compound is highly hydrophobic and its limited oral bioavailability has hindered its clinical translation. In this study, we encapsulated SR13668 into polymeric nanoparticles to increase compound aqueous solubility and therefore bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (100-200 nm) encapsulating SR13668 with narrow size distribution and high drug loading were generated by a continuous and scalable process of flash nanoprecipitation integrated with spray dry. A single gavage dose of SR13668-PLGA nanoparticles at 2.8 mg/kg was administered in eight beagle dogs. Drug levels in animal whole blood and plasma were measured over 24 hours. Enhanced bioavailability of SR13668 using nanoparticles compared with formulations of Labrasol® and neat drug in 0.5% methylcellulose is reported. This is the first attempt to study pharmacokinetics of SR13668 in large animals with orally administrated nanoparticle suspension.

Evaluation of the effect of compound aqueous solubility in cytochrome P450 inhibition assays

It is a common practice in drug discovery organizations to screen new chemical entities in order to predict future drug-drug interactions. For this purpose, there are two main assay strategies, one based on recombinant cytochrome P450 (rCYP) enzymes and fluorescent detection, and other on human liver microsomes (HLM) and liquid chromatography coupled to mass spectrometry. Many authors have reported a poor correlation between both technologies, giving rise to concerns about the usefulness of fluorometric methods for predicting drug-drug interactions. In this study, we investigated the role that compound aqueous kinetic solubility may play in this lack of correlation. We found that drug discovery compounds with unacceptable kinetic solubility, measured by a turbidimetric solutibility assay, tended to yield higher IC50 values in in vitro models based on human liver microsomes, whereas compounds with kinetic solubility values higher than 50 μM showed very similar IC50 values in both in vitro models. Our results show that the turbidimetric solubility assay is a useful tool to identify those discovery compounds that may require further investigation in order to avoid overlooking future drug-drug interactions.

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

Aqueous solubility is an important physicochemical parameter for any potential drug candidate, and high-throughput kinetic assays are frequently used in drug discovery to give an estimate of a compound's aqueous solubility. However, the aqueous solubility data from an equilibrium (thermodynamic) shake-flask technique is considered more relevant, but is slower and more labor intensive to generate. A highly automated aqueous equilibrium solubility shake-flask technique is described and validated on a set of 15 marketed drugs, whose aqueous solubilities cover four orders of magnitude. The assay uses a Tecan Freedom Evo 200 liquid handling robot (Tecan Group Ltd., Männerdorf, Switzerland) with integrated appliances for the transportation, decapping and recapping, and centrifugation of sample tubes. These bespoke automation solutions help overcome the labor intensive steps associated with performing conventional, gold standard, aqueous equilibrium solubility shake-flask measurements, enabling the assay to be used as a primary-wave drug discovery screen.

Compound-class specific estimation of solid organic compound vapour pressure and aqueous solubility from simple molecular structure descriptors and the temperature of melting

For many solid organic compounds, experimental data for their aqueous solubility and vapour pressure are lacking. Therefore, estimation procedures for these compound properties are needed. On theoretical grounds, this study derives a general compound-class specific estimation procedure for solid organic compound aqueous solubility and vapour pressure. The estimation procedure uses a linear combination of simple molecular descriptors for the molecular structure variation within the compound class and a polynomial for the temperature of melting. This procedure is applied to the vapour pressure of polycyclic aromatic hydrocarbons (PAHs), alkylated PAHs, polychlorinated dibenzo- p-dioxins and biphenyls and to the aqueous solubility of PAHs, methylated PAHs, chlorinated benzenes, polychlorinated and polybrominated biphenyls, chlorinated phenols, cresols, and chlorinated 2-methoxyphenols. The standard error of the solid vapour pressure or aqueous solubility estimates from the various compound-class specific regression equations was about 0.2 log units. For PAHs, chlorobenzenes, and PCBs used in the present study, aqueous solubility estimated from the regression equations taking the temperature of melting equal to 298 K, i.e. assuming that the compounds are in a hypothetical liquid state, was equal, within 0.1–0.3 log units to the subcooled liquid solubility estimated from literature regression equations.

Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a Potent and Orally Available Hepatitis C Virus Polymerase Inhibitor

The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.

Nanosizing of a drug/carrageenan complex to increase solubility and dissolution rate

In this study, we present a novel approach of nanosizing a drug/polymeric complex to increase both solubility and dissolution rate of poorly water-soluble compounds. A hydrophilic polymer, lambda-carrageenan, was first complexed with a model poorly water-soluble compound to increase the compound's aqueous solubility. The compound/carrageenan complex was further nanosized by wet-milling to enhance the dissolution rate. By complexing with carrageenan, the compound became amorphous in the complex. Using additional carrageenan as a stabilizer for nanosizing, a nanosuspension of a compound/carrageenan complex with a median particle size of about 0.3 μm was successfully developed. The particle size of the nanosuspension did not increase significantly during the lyophilization process and was stable for at least 39 days at room temperature after lyophilization. This approach of nanosizing a drug/carrageenan complex increased the aqueous solubility of the compound from less than 1 μg/mL to 39 μg/mL. In addition to increasing aqueous solubility, a nanosized compound/carrageenan complex had a faster dissolution rate than the complex, the free compound, and the nanosuspension of the free compound.

Technetium and Molybdenum in Oxide Spent Nuclear Fuel: Impact on Release Estimates

AbstractTechnetium-99 99Tc) is an important radionuclide in repository models owing to its relatively long half-life and the high aqueous solubility of compounds where it is inthe heptavalent state. The vast majority of the 99Tc inventory presently slatedfor disposal is contained in oxide commercial spent nuclear fuel (CSNF), where it is divided (along with its cohort, molybdenum) betweenexsolved, intermetallic “epsilon” particles and isolated, likely oxidized, atoms distributed in the uranium dioxide matrix. We present recent evidence from synchrotron x-ray fluorescence spectroscopy, electron microscopy, and fuel dissolution testing on the likely oxidation state, coordination environment, and physical disposition of technetium and molybdenum in CSNF. Effects of the relative proportioningof technetium and molybdenum among the metallic and oxidized states in CSNF, andtheir distribution in or near grain boundaries and gaps on release during CSNF corrosion testing are discussed.

The Zero Time Dynamic Interfacial Tension

ABSTRACT It has been shown earlier that interfacial tensions between organic liquids and a polar liquid such as water, when measured by drop shape (or drop weight) analysis only closely relate to the mutual solubility of the two liquids as well as to the free energies of interaction between and in the two liquids, when using completely apolar liquids such as alkanes. In all other cases, with partly polar liquids (even including aromatic compounds), the interfacial tension with water (as relates to the mutual solubility of the two liquids) is significantly underestimated by this method, due to unavoidable hysteresis caused by the almost instantaneous orientation of the polar moieties of the organic compound toward the water interface. It is therefore appropriate to introduce the concept of zero time dynamic (ZTD) interfacial tension, where ZTD interfacial tension is designated as γij o. Now, two methods for determining ZTD interfacial tensions between polar condensed-phase compounds and water correlate closely to solubilities as well as to free energies of interaction. The first one relates the compound's aqueous solubility to its contactable surface area and its ZTD interfacial tension with water. This approach also allows the determination of ZTD interfacial tensions with very water-soluble solutes, such as sugars. The second one (able to furnish ZTD interfacial tensions between any two condensed-phase materials) utilizes the results of contact angle measurements, interpreted via the Young–Dupré equation, combined with the van Oss–Chaudhury–Good equation for interfacial tension. In some cases the latter approach can be circumvented by using the original Young equation. From the solubility of water in a number of organic solvents, the contactable surface area could be determined for water clusters, at 20ˆC, at about 4.5 monomeric water molecules per cluster.

Estimating the aqueous solubilities of individual chlorinated n‐alkanes (C10–C12) from measurements of chlorinated alkane mixtures

AbstractWater solubilities of several chlorinated n‐alkanes, with carbon chain lengths ranging from C10 to C12, were determined from simple synthetic mixtures because few of these compounds are available in pure form. The apparent solubilities (S′w) of several chlorinated n‐decanes in the mixture were determined using the generator column technique. To assess the effect of the mixture on S′w, the aqueous solubility and activity coefficient (γorg) of a reference compound, 1,10‐dichlorodecane, were determined as a function of its mole fraction in the same synthetic mixture. The mixture exhibited a cosolute effect on the solubility of dichlorodecane, with apparent solubilities decreasing linearly with decreasing mole fraction. The results were used to correct the apparent solubilities of terra‐ and pentachlorodecanes determined from the synthetic mixture, thereby providing estimates of the true subcooled‐liquid aqueous solubilities of these compounds. The solubilities of polychlorinated decane, undecane, and dodecane congeners were also estimated using subcooled‐liquid vapor pressures and Henry's law constants determined from previous experiments. The two methods yielded comparable estimates, within a factor of 1.5, of the true solubilities of polychlorinated decanes. Water solubilities for selected chlorinated n‐alkane congeners among the three carbon chain lengths ranged from 22.4 to 975 μg/L and showed a trend of increasing solubility with increasing degree of chlorination to chlorine number five. The data, providing some of the first physical properties of individual isomers of C10 to C12 polychlorinated n‐alkanes, may be useful in assessing the environmental behavior of chlorinated paraffins in general.

Isocratic chromatographic retention data for estimating aqueous solubilities of acidic, basic and neutral drugs

For 108 compounds of diverse chemical character (including drug molecules) isocratic reversed-phase liquid chromatographic retention parameters have been used in modifications of the Hildebrand-Scott equation to estimate compound aqueous solubility. The relationships found are valid for both liquids and crystalline solids, as well as for stronger ( pK a > 6.5) bases that are chromatographed in a partially ionized state. It is observed that there is a significant constant difference in behaviour between acid and alcohol molecules and neutral and base molecules. This difference can be empirically corrected for during solubility estimations. Comparison of the use of octan-l-ol/water distribution coefficients in these equations shows that the use of isocratic chromatograhic retention parameters lead to significantly better estimations of compound aqueous solubility.