QSAR Research Articles

Elucidation of molecular mechanisms involved in tadpole toxicity employing QSTR and q-RASAR approach

Tadpoles, as early developmental stages of frogs, are vital indicators of toxicity and environmental health in ecosystems exposed to harmful organic compounds from industrial and runoff sources. Evaluating each compound individually is challenging, necessitating the use of in-silico methods like Quantitative Structure Toxicity Relationship (QSTR) and Quantitative Read-Across Structure Activity Relationship (q-RASAR). Utilizing the comprehensive US EPA's ECOTOX database, which includes acute LC50 toxicity and chronic endpoints, we extracted crucial data such as study types, exposure routes, and chemical categories. Regression-based QSTR and q-RASAR models were developed from this dataset, emphasizing key chemical descriptors. Lipophilicity and unsaturation were significant for predicting acute toxicity, while electrophilicity, nucleophilicity, and molecular branching were crucial for chronic toxicity predictions. Additionally, q-RASAR models integrated with the "intelligent consensus" algorithm were employed to enhance predictive accuracy. The performance of these models was rigorously compared across various approaches. These refined models not only predict the toxicity of untested compounds but also reveal underlying structural influences. Validation through comparison with existing literature affirmed the relevance and robustness of our approach in ecotoxicology.

An automated computational data pipeline to rapidly acquire, score, and rank toxicological data for ecological hazard assessment.

Biological Evaluations support Endangered Species Act (ESA) consultation with the US Fish and Wildlife Service and National Marine Fisheries Service by federal action agencies, such as the USEPA, regarding impacts of federal activities on threatened or endangered species. However, they are often time-consuming and challenging to conduct. The identification of pollutant benchmarks or guidance to protect taxa for states and tribes when USEPA has not yet developed criteria recommendations is also of importance to ensure a streamlined approach to Clean Water Act program implementation. Due to substantial workloads, tight regulatory timelines, and the often-protracted length of ESA consultations, there is a need to streamline the development of biological evaluation toxicity assessments for determining the impact of chemical pollutants on ESA-listed species. Moreover, there is limited availability of species-specific toxicity data for many contaminants, further complicating the consultation process. New approach methodologies are being increasingly used in toxicology and chemical safety assessment to rapidly and cost-effectively provide data that can fill gaps in hazard and/or exposure characterization. Here, we present the development of an automated computational pipeline-RASRTox (Rapidly Acquire, Score, and Rank Toxicological data)-to rapidly extract and categorize ecological toxicity benchmark values from curated data sources (ECOTOX, ToxCast) and well-established quantitative structure-activity relationships (TEST, ECOSAR). As a proof of concept, points-of-departure (PODs) generated in RASRTox for 13 chemicals were compared against benchmark values derived using traditional methods-toxicity reference values (TRVs) and water quality criteria (WQC). The RASRTox PODs were generally within an order of magnitude of corresponding TRVs, though less concordant compared with WQC. The greatest utility of RASRTox, however, lies in its ability to quickly and systematically identify critical studies that may serve as a basis for screening value derivation by toxicologists as part of an ecological hazard assessment. As such, the strategy described in this case study can potentially be adapted for other risk assessment contexts and stakeholder needs. Integr Environ Assess Manag 2024;20:2203-2217. © 2024 Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Non-targeted screening and toxicity study of safety risk substances in facial skincare products: Molecular networking and computational toxicology strategy

BackgroundRisk substances in cosmetics have long been associated with adverse reactions. However, as risk substances become more concealed and diversified, conventional targeted analysis methods are no longer sufficient to meet regulatory requirements. ObjectiveTo construct a rapid and effective non-targeted screening method for the identification of risk substances, and to provide a high-throughput method for toxicity assessment. MethodsMolecular networking was utilized for the non-targeted screening of risk substances in facial skincare products, and the toxicity of these risk substances was evaluated through molecular docking and quantitative structure-activity relationship (QSAR) models. ResultsThrough molecular networking, we identified seven known prohibited ingredients, six of which were confirmed using standard substances. In addition, 17 potential risk substances were discovered within molecular clusters containing prohibited ingredients, including antibiotics, antihistamines, and phthalates, etc. Notably, chloramphenicol base and N-desmethyl chlorpheniramine exhibited stronger binding affinity to keratin 5/14 than chloramphenicol and chlorpheniramine through molecular docking, respectively. Additionally, toxicity prediction results indicated that the carcinogenicity of antibiotics presented gender differences in mice and rats, and two chlorpheniramine derivatives also showed carcinogenicity in mice. Moreover, of the 24 compounds, 11 showed skin sensitization, while 14 caused skin irritation. Furthermore, half of these compounds demonstrated potential developmental toxicity, and only 4-nitrobenzenethiol was found to be mutagenic. ConclusionIn this study, we developed a visualization strategy for non-targeted screening of risk substances and a high-throughput method for initial toxicity assessment of risk substances.

Application of computer-aided drug design in drug discovery and development: Updating knowledge

Coronavirus (CoV) diseases are widespread throughout the world and have caused considerable socio-economic disruptions. For this reason, efforts have been made to develop a direct or indirect antiviral drugs against these diseases. However, no specific antiviral drug has yet been approved by the Food and Drug Administration (FDA) for CoV infections. Thus, the challenge in discovering therapeutic molecules against these infections remains pertinent. Computer-aided drug design (CADD) is one of the modern techniques for drug discovery and development. It accelerates the process, minimizes costs, and reduces research time. In this article, we present the three CADD approaches, namely structure-based drug discovery (SBDD), ligand-based drug discovery (LBDD) and high-throughput virtual screening (HTVS). The different methods used in these three approaches CADD, such as molecular modelling, target structure analysis, molecular docking, molecular dynamics simulation, pharmacophore modelling, quantitative structure-activity relationship (QSAR), ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) are detailed. In addition, the bioinformatics tools and databases commonly used in these different CADD techniques are also described.

QSAR Regression Models for Predicting HMG-CoA Reductase Inhibition

Background/Objectives: HMG-CoA reductase is an enzyme that regulates the initial stage of cholesterol synthesis, and its inhibitors are widely used in the treatment of cardiovascular diseases. Methods: We have created a set of quantitative structure-activity relationship (QSAR) models for human HMG-CoA reductase inhibitors using nested cross-validation as the primary validation method. To develop the QSAR models, we employed various machine learning regression algorithms, feature selection methods, and fingerprints or descriptor datasets. Results: We built and evaluated a total of 300 models, selecting 21 that demonstrated good performance (coefficient of determination, R2 ≥ 0.70 or concordance correlation coefficient, CCC ≥ 0.85). Six of these top-performing models met both performance criteria and were used to construct five ensemble models. We identified the descriptors most important in explaining HMG-CoA inhibition for each of the six best-performing models. We used the top models to search through over 220,000 chemical compounds from a large database (ZINC 15) for potential new inhibitors. Only a small fraction (237 out of approximately 220,000 compounds) had reliable predictions with mean pIC50 values ≥ 8 (IC50 values ≤ 10 nM). Our svm-based ensemble model predicted IC50 values < 10 nM for roughly 0.08% of the screened compounds. We have also illustrated the potential applications of these QSAR models in understanding the cholesterol-lowering activities of herbal extracts, such as those reported for an extract prepared from the Iris × germanica rhizome. Conclusions: Our QSAR models can accurately predict human HMG-CoA reductase inhibitors, having the potential to accelerate the discovery of novel cholesterol-lowering agents and may also be applied to understand the mechanisms underlying the reported cholesterol-lowering activities of herbal extracts.

Selective Metal‐Coordinated Nanodrugs Based on Thiazine Moiety for Anticancer Therapeutics: Spectroscopic, Theoretical, and Molecular Docking Studies

ABSTRACTThe current study involved production, comprehensive structural analysis, and physicochemical characterizing of two distinctive complexes namely, Cu(TBH) and Zn(TBH); TBH donor ligand: N′‐(1‐(3,6‐dihydro‐4‐hydroxy‐2,6‐dioxo‐2H‐1,3‐thiazin‐5‐yl)ethylidene)‐2‐hydroxybenzohydrazide) using a wide range of analytical methods, including elemental analysis, UV–Vis, FT‐IR, and 1HNMR spectrometry, molar conductivity and magnetic susceptibility measurements, and thermal analysis. According to the findings, chelation can occur through O, N, and O donor atoms of monoanionic chelator for generating mono‐nuclear chelates with tetrahedral geometry for Cu (II) and octahedral geometry for Zn (II). The anticarcinogenic ability of TBH chelator and its coordinated compounds against human liver cancer (HepG‐2) was investigated. The Cu(TBH) complex was found to have selective and promising anticancer activity against a liver cancer cell line, with lower IC50 (liver carcinoma cell line) and higher IC50 (normal human cell line) values than other produced compounds and standard drugs. Utilizing DFT computations, the molecular structures of the TBH and its complexes were verified, offering a detailed understanding of their quantum chemical characteristics. A quantitative structure–activity relationship (QSAR) model, which illustrates the association between DFT‐computed descriptors and biological activities pIC50, was also created using multiple linear regression (MLR) on the synthesized compounds as anticancer medicines. Additionally, there are no issues with the produced compounds' oral bioavailability according to (ROF) Lipinski's rule of five. Furthermore, docking studies of the synthesized TBH chelator and its chelates with CDK2 kinase have been performed to validate the biological findings. According to our findings, the novel Cu(TBH) nanodrug exhibits considerable cytotoxic activity, prompting further study into its pharmacological profile and exploring its potential in drug development.

Ornidazole degradation based on peroxymonosulfate activation induced by oxygen vacancies (OV)-enriched Cu-Co-TiO2: Coexistence of free-radical and non-radical pathways

Employing transition-metal catalysts in peroxymonosulfate (PMS) activation reactions to facilitate combined free-radical and non-radical interactions is regarded as a proficient approach for decomposing organic contaminants. However, the creation of active catalysts faces significant challenges due to low activation efficiency, inadequate action sites, and instability of current activation materials. Here, we successfully prepared bimetallic Cu and Co co-doped TiO2 (Cu-Co-TiO2) catalyst using the sol-gel technique. Excellent ornidazole (ONZ) removal efficiency (0.628 min−1) was demonstrated by the Cu-Co-TiO2/PMS system, which was applicable across a broad pH range (4−10) and unaffected by different water matrices. Moreover, the coexistence of free-radical (SO4•-, •OH and O2•−) and non-radical (1O2) routes in the Cu-Co-TiO2/PMS system, where SO4•- and 1O2 are the predominant active substances, was confirmed by quenching experiments and electron paramagnetic resonance (EPR) study. The synergistic impact of Cu/Co bimetal may hasten the redox cycles of Cu+/Cu2+ and Co2+/Co3+, causing plenty of oxygen vacancies (OV) and improving PMS activation efficiency. The quantitative structure-activity relationship (QSAR) examination of the intermediates showed a decrease in toxicity, and the potential pathways of ONZ degradation were illustrated using Liquid Chromatography Mass Spectrometry (LC-MS) technology. This work not only demonstrated the effectiveness and stability of Cu-Co-TiO2 as a PMS activator, but it also offered fresh information on how to remove organic pollutants from wastewater by using PMS activation via the radical and non-radical oxidation pathway.

Optimizing predictive models for evaluating the F-temperature index in predicting the π-electron energy of polycyclic hydrocarbons, applicable to carbon nanocones

In the fields of mathematics, chemistry, and the physical sciences, graph theory plays a substantial role. Using modern mathematical techniques, quantitative structure-property relationship (QSPR) modeling predicts the physical, synthetic, and natural properties of substances based only on their chemical composition. For a chemical graph, the temperature of a vertex is a local property introduced by Fajtlowicz (1988). A temperature-based graphical descriptor is structured based on temperatures of vertices. Involving a non-zero real parameter β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document}, the general F-temperature index Tβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$T_{\\beta }$$\\end{document} is a temperature index having strong efficacy. In this paper, we employ discrete optimization and regression analysis to find optimal value(s) of β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document} for which the prediction potential of Tβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$T_{\\beta }$$\\end{document} and the total π\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\pi$$\\end{document}-electron energy Eπ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$E_{\\pi }$$\\end{document} of polycyclic hydrocarbons is the strongest. This, in turn, answers an open problem proposed by Hayat & Liu (2024). Applications of the optimal values for Tβ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$T_{\\beta }$$\\end{document} are presented a two-parametric family of carbon nanocones in predicting their Eπ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$E_{\\pi }$$\\end{document} with significantly higher accuracy.

Application of Machine Learning in the Development of Fourth Degree Quantitative Structure-Activity Relationship Model for Triclosan Analogs Tested against Plasmodium falciparum 3D7.

Despite new therapies against malaria, this disease remains one of the main causes of death affecting humanity. The phenomenon of resistance has caused concern as the drugs no longer have the same efficacy, forcing scientific research to develop new methods that prospect new molecules. With the advancement of artificial intelligence, it becomes possible to apply machine learning (ML) techniques in the discovery and evaluation of new molecules, by employing the quantitative structure-activity relationship (QSAR), a classic method that uses regressions to create a model that allows identifying and evaluating new drug candidates. This work combined QSAR with ML and developed a supervised model that modeled a fourth degree polynomial equation capable of identifying new drug candidates derived from the triclosan compound-a classic inhibitor of Plasmodium falciparum growth, the cause of severe malaria. The model produces an R 2 greater than 80% for training and concurrent testing, as well as a correlation index greater than 80% between the calculated and experimental pEC50 (negative logarithm of half maximal effective concentration) data. In addition, a web software (PlasmoQSAR) was created that allows researchers to calculate the EC50 (half maximal effective concentration) of new molecules using the developed analytical method.

Aromatase as a novel target of parabens in human and rat placentas: 3D-quantitative structure-activity relationship and docking analysis

Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC50 values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC50 values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC50 values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.

Photocatalytic hydrogen production and sulfamerazine degradation via a novel dual S-scheme photocatalyst: Nanocomposite synthesis, characterization and mechanism insights

Creating highly effective photocatalysts is crucial for harnessing solar energy to degrade pollutants and produce hydrogen (H₂). In this study, we successfully synthesized a novel dual S-scheme iron oxide (Fe₂O₃)/bismuth oxide (Bi₂O₃)/titanium dioxide (TiO₂) ternary photocatalyst using a straightforward method. This photocatalyst was employed for efficient photocatalytic water splitting and the degradation of the antibiotic sulfamerazine (SMZ) under visible light. Various characterization and photoelectrochemical techniques, including scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), Brunauer–Emmett–Teller surface area analysis (BET), photocurrent measurements, Mott-Schottky analysis, photoluminescence (PL), electrochemical impedance spectroscopy (EIS), and electron spin resonance (ESR), were utilized to analyze the synthesized materials. Among the synthesized nanocomposites, the 15 wt% Fe₂O₃/Bi₂O₃/TiO₂ (15FeBi/TiO₂) composite demonstrated exceptional photocatalytic efficiency, achieving 98 % SMZ degradation and a hydrogen production rate of 590.36 μmol/g·h. Experimental results, including scavenging tests and ESR findings, highlighted the crucial role of hydroxyl radicals (•OH) and superoxide radicals (•O₂−) in the photocatalytic process. Moreover, liquid chromatography-mass spectrometry (LC-MS) results proposed three degradation pathways, and quantitative structure-activity relationship (QSAR) analysis showed that the toxicity of intermediates was effectively reduced. The 15FeBi/TiO₂ photocatalyst also exhibited excellent reusability, retaining about 85 % of its initial activity after five cycles, and proved effective against various pollutants and in real water matrices. This research contributes to the design and development of high-activity heterojunction photocatalysts for superior clean energy generation and pollutant degradation under visible light.

Understanding the potential of coal gangue as photocatalyst for antibiotic degradation: The role of abundant oxygen vacancies and electron-hole pairs

Coal gangue (CG) offers promising potential as a cost-effective photocatalyst for antibiotic degradation. However, current approaches do not emphasize the origin of its photocatalytic activity. This study investigates the photocatalytic activity of CG through a comparative analysis with one-pot aerobic/anaerobic calcinated CG. The potential application of CG as a photocatalyst for tetracycline (TC) decontamination in water was evaluated under dark and light. Characterization results identified anatase and kaolinite as the critical photosensitive minerals in CG. Batch removal experiments indicated that CG achieved up to 98 % TC removal at 1 g/L dosage, with most biotoxic intermediates reduced to below 0.9 mg L−1 Lethal Concentration 50 (LC50) of Fathead minnow (Pimephales promelas). Degradation pathways identified by density functional theory (DFT) and quantitative structure-activity relationship (QSAR) indicated that superoxide anion (⁎O2−) and electron-hole (e−-h+) pairs were predominant contributors to TC photodegradation. Theoretical calculations suggest that the oxygen vacancies on the CG surface can accelerate the production of ⁎O2−, while fast electron transport channels within surface hydroxyl groups facilitate e− and h+ separation. The findings of this research elucidate the origin of CG's photocatalytic activity and highlight the potential to serve as a photocatalyst for low-cost antibiotic removal, offering a promising solution for coal waste management and utilization.

In Silico Design of Novel Piperazine-Based mTORC1 Inhibitors Through DFT, QSAR and ADME Investigations

Mammalian target of rapamycin complex 1 (mTORC1) is an important and promising alternative biological target for the treatment of different types of cancer including breast, lung and renal cell carcinoma. This study contributed to the development of mathematical models highlighting the quantitative structure-activity relationship of a series of piperazine derivatives reported as mTORC1 inhibitors. Various molecular descriptors were calculated using Gaussian 09, Chemsketch, and ChemOffice software. The density funcional theory (DFT) method at the level B3LYP/6-31G+(d, p) was applied to determine the structural, electronic and energetic parameters associated with the studied molecules. The predictive ability of the built models, which is obtained by two methods (MLR and MNLR), showed that the built models are statistically significant. The QSAR modeling results revealed that the six molecular descriptors of lowest unoccupied molecular orbital energy (ELUMO), electrophilicity index (ω), molar refractivity (MR), aqueous solubility (Log S), topological polar surface area (PSA), and refractive index (n) significantly correlated to the biological inhibitory activity of piperazine derivatives. Using QSAR models and in silico pharmacokinetic profiles predictions, five new candidate compounds are selected as potential inhibitors against cancer.

Effect of glycerin on the physical properties of polyvinyl alcohol/sodium alginate blend

Because of the abundance of sodium resources, sodium-ion batteries (NIBs) offer a promising alternative electrochemical energy storage solution. One of the current roadblocks to the development of NIBs technology is a lack of electrode materials capable of reversibly storing/releasing sodium ions for a sufficiently long time. Thus, this work aims to study, theoretically, the effect of glycerin incorporation on polyvinyl alcohol (PVA)/sodium alginate (Na Alg) blend as electrode materials for NIBs. The electronic, thermal, and quantitative structure-activity relationship (QSAR) descriptors of polymer electrolytes based on a blend of PVA and Na Alg and glycerin are the main topics of this work. These properties are examined here using semi-empirical methods and the density functional theory (DFT). Bandgap energy (Eg) is examined because the structural analysis reveals details regarding the interactions between PVA/Na Alg and glycerin. The findings indicate that the addition of glycerin caused the Eg value to drop to 0.2814 eV. The molecular electrostatic potential surface, or MESP, shows the electron-rich and deficit regions throughout the electrolyte system as well as the distribution of molecular charges. Thermal parameters that are studied include enthalpy (H), entropy (ΔS), heat capacity (Cp), Gibbs’ free energy (G), and heat of formation. Additionally, the study examines several QSAR descriptors, such as total dipole moment (TDM), total energy (E), ionization potential (IP), Log P, and Polarizability. The results show that H, ΔS, Cp, G, and TDM increased with increasing temperature and glycerin content. Meanwhile, heat of formation, IP, and E decreased, improving reactivity and polarizability. Additionally, the cell voltage increased to 2.488 V due to glycerin addition. The overall DFT and PM6 calculations of cost-effective PVA/Na Alg based glycerin electrolytes indicate that they can partially replace lithium-ion batteries due to their multifunctionality, but requires further improvement and investigations.

Novel "Phenyl-Pyrazoline-Oxadiazole" Ternary Substructure Derivatives: Synthesis, Insecticidal Activities, and Structure-Activity Relationship Study.

In recent years, isoxazole insecticides or parasiticides targeting the γ-aminobutyric acid receptor, such as fluralaner or fluxametamide, featured a novel chemical structure and exhibited potent insecticidal activity with no-cross resistance. Thus, many research institutes have tried to modify the structures of these agents to find a new insecticide. Previously, the majority of researchers stuck to the "phenyl-isoxazole-phenyl" structure, making modifications only to other components. In this study, the "phenyl-isoxazole-phenyl" ternary motif was modified for the first time based on bioisosterism theory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole moieties were designed and synthesized to investigate their insecticidal activities against the diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against P. xylostella and S. frugiperda. Especially, compound A21 showed insecticidal activity against P. xylostella (LC50 = 1.2 μg/mL) better than commercial insecticide ethiprole (LC50 = 2.9 μg/mL) but worse than parasiticide fluralaner (LC50 = 0.5 μg/mL). Similarly, compound A21 exhibited insecticidal activity to S. frugiperda (LC50 = 13.2 μg/mL) better than commercial insecticide fipronil (LC50 = 78.8 μg/mL) but worse than fluralaner (LC50 = 0.7 μg/mL). Compound A21 could serve as a potential lead compound to control P. xylostella and S. frugiperda. The three-dimensional quantitative structure-activity relationship model revealed that the further introduction of an electron-donating group in the 2- or 3-site may increase the insecticidal activity of A21. Molecular dynamics simulations showed that the hydrogen bond of A21 and receptor was important for the binding receptor. This study has identified a new substructure called "phenyl-pyrroline-oxadiazole" instead of the previously known "phenyl-isoxazole-phenyl" substructure, offering a useful guide for the design of novel insecticide molecules.

Computational Study of Coumarin Compounds as Potential Inhibitors of Casein Kinase 2: DFT, 2D-QSAR, ADMET and Molecular Docking Investigations

Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, there has been a notable increase in interest in the use of casein kinase 2 (CK2) inhibitors to improve the treatment of a specific form of cancer while minimizing the risk of undesirable side effects. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that the coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, quantitative structure-activity relationship (QSAR) analysis has been employed to envisage the inhibitory effects of 32 coumarin derivatives on the CK2 protein. The most efficient model is found by using multiple linear regression (MLR). Its capability is considered by the external and internal validation values found (R2 = 0.884, Q2cv = 0.822, R2pred = 0.821, and R2p = 0.811), which aligned well with Tropsha and Golbraikh’s approach. The highest docking score founded for the newly designed coumarins is −7.50 kcal mol-1, which indicates that candidates can bind to the CK2 receptor with greater affinity. Based on the results of the ADMET properties and drug similarity analyses, a DFT investigation was conducted to confirm the stability of the newly explored compounds. It appears that the most stable complexes are those of compound with the highest binding affinity with a lower risk of toxicité.

Emodin derivatives as novel potent DPP-4 inhibitors: Design, synthesis, and in vitro evaluation

Dipeptidyl peptidase-4 (DPP-4) inhibitors have gained recognition as effective agents for lowering blood sugar levels, significantly improving glycemic control for individuals with type 2 diabetes mellitus (T2DM). Emodin, an anthraquinone derived from the traditional herbs rhubarb (Rheum officinale) and Polygonum cuspidatum, has been identified as an important component in the development of new treatments for diabetes. In the present work, we explored the DPP-4 inhibitory activity of emodin derivatives. This study focused on the design, synthesis, and evaluation of emodin derivatives for their in vitro DPP-4 inhibitory activity. Molecular docking studies indicated that 3-o-toluoyl emodin (OTEM) had the lowest docking score (−134.073) against the DPP-4 protein among the tested compounds. OTEM also achieved the highest drug-likeness score of 0.56 and demonstrated DPP-4 inhibitory activity, with an IC50 value of 0.77 μM. Furthermore, structure-activity relationship (SAR) analysis suggested that the addition of an ortho-toluoyl group at the C-3 position could enhance DPP-4 inhibition. Additionally, quantitative structure-activity relationship (QSAR) model assessments revealed that log P was the only descriptor significantly influencing DPP-4 inhibitory activity. Therefore, the current study indicates that OTEM could serve as a promising lead compound to address the demand for antidiabetic agents.

Advancing Breathomics through Accurate Discrimination of Endogenous from Exogenous Volatiles in Breath.

Breathomics, a growing field in exposure monitoring and clinical diagnostics, has faced accuracy challenges due to unclear contributing factors. This study aims to enhance the potential of breathomics in various frontiers by categorizing exhaled volatile organic compounds (VOCs) as endogenous or exogenous. Analyzing ambient air and breath samples from 271 volunteers via TD-GC × GC-TOF MS/FID, we identify and quantify 50 common VOCs in exhaled breath. Advanced quantitative structure-property relationships and compartment models are employed to obtain VOCs kinetic parameters. This in-depth approach allows us to accurately determine the alveolar concentration of VOCs and further discern their origins, facilitating personalized application of breathomics in exposure assessment and disease diagnosis. Our findings demonstrate that prolonged external exposure turns humans into secondary pollutant sources. Analysis of endogenous VOCs reveals that internal exposure poses more significant health risks than external. Moreover, by correcting environmental backgrounds, we improve the accuracy of gastrointestinal disease diagnostic models by 15-25%. This advancement in identifying VOC origins via compartmental models promises to elevate the clinical relevance of breathomics, marking a leap forward in exposure assessment and precision medicine.

Machine Learning-Based In Silico Prediction of the Inhibitory Activity of Chemical Substances Against Rat and Human Cytochrome P450s.

The prediction of cytochrome P450 inhibition by a computational (quantitative) structure-activity relationship approach using chemical structure information and machine learning would be useful for toxicity research as a simple and rapid in silico tool. However, there are few in silico models focusing on the species differences between rat and human in the P450s inhibition. This study aimed to establish in silico models to classify chemical substances as inhibitors or non-inhibitors of various rat and human P450s, using only molecular descriptors. Using the in-house test results from our in vitro experiments, we used 326 substances for model construction and internal validation data. Apart from the 326 substances, 60 substances were used as external validation data set. We focused on seven rat P450s (CYP1A1, CYP1A2, CYP2B1, CYP2C6, CYP2D1, CYP2E1, and CYP3A2) and 11 human P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Most of the models established using XGBoost showed an area under the receiver operating characteristic curve (ROC-AUC) of 0.8 or more in the internal validation. When we set an applicability domain for the models and confirmed their generalization performance through external validation, most of the models showed an ROC-AUC of 0.7 or more. Interestingly, for CYP1A1 and CYP1A2, we discovered that a human P450 inhibitory activity model can predict rat P450 inhibitory activity and vice versa. These models are the first attempts to predict inhibitory activity against a wide variety of P450s in both rats and humans using chemical structure information. Our experimental results and in silico models would be helpful to support information for species similarities and differences in chemical-induced toxicity.

Impact of gut permeability on estimation of oral bioavailability for chemicals in commerce and the environment.

Performance of pharmacokinetic models developed using in vitro-to-in vivo extrapolation (IVIVE) methods may be improved by refining assumptions regarding fraction absorbed (Fabs) through the intestine, a component of oral bioavailability (Fbio). Although in vivo measures of Fabs are often unavailable for non-pharmaceuticals, in vitro measures of apparent permeability (Papp) using the Caco-2 cell line have been highly correlated with Fabs. We measured bidirectional Papp for over 400 non-pharmaceutical chemicals using the Caco-2 assay. A random forest quantitative structure-property relationship (QSPR) model was developed using these and peer-reviewed pharmaceutical data. Both Caco-2 data (R²=0.37) and the QSPR model (R²=0.29) were better at predicting human bioavailability compared to in vivo rat data (R²=0.23). After incorporation into a high throughput toxicokinetics (HTTK) framework for IVIVE, the Caco-2 data were used to estimate in vivo administered equivalent dose (AED) for bioactivity assessed in vitro, The HTTK-predicted plasma steady state concentrations (Css) for IVIVE were revised, with modest changes predicted for poorly absorbed chemicals. Experimental data were evaluated for sources of measurement uncertainty, which were then accounted for using the Monte Carlo method. Revised AEDs were subsequently compared with exposure estimates to evaluate effects on bioactivity:exposure ratios, a surrogate for risk. Only minor changes in the margin between chemical exposure and predicted bioactive doses were observed due to the preponderance of highly absorbed chemicals.