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1.
Mol Divers ; 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38460065

RESUMEN

Contemporary research has convincingly demonstrated that upregulation of G protein-coupled receptor 183 (GPR183), orchestrated by its endogenous agonist, 7α,25-dihydroxyxcholesterol (7α,25-OHC), leads to the development of cancer, diabetes, multiple sclerosis, infectious, and inflammatory diseases. A recent study unveiled the cryo-EM structure of 7α,25-OHC bound GPR183 complex, presenting an untapped opportunity for computational exploration of potential GPR183 inhibitors, which served as our inspiration for the current work. A predictive and validated two-dimensional QSAR model using genetic algorithm (GA) and multiple linear regression (MLR) on experimental GPR183 inhibition data was developed. QSAR study highlighted that structural features like dissimilar electronegative atoms, quaternary carbon atoms, and CH2RX fragment (X: heteroatoms) influence positively, while the existence of oxygen atoms with a topological separation of 3, negatively affects GPR183 inhibitory activity. Post assessment of true external set prediction capability, the MLR model was deployed to screen 12,449 DrugBank compounds, followed by a screening pipeline involving molecular docking, druglikeness, ADMET, protein-ligand stability assessment using deep learning algorithm, molecular dynamics, and molecular mechanics. The current findings strongly evidenced DB05790 as a potential lead for prospective interference of oxysterol-mediated GPR183 overexpression, warranting further in vitro and in vivo validation.

2.
Regul Toxicol Pharmacol ; 148: 105572, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38325631

RESUMEN

We have modeled here chronic Daphnia toxicity taking pNOEC (negative logarithm of no observed effect concentration in mM) and pEC50 (negative logarithm of half-maximal effective concentration in mM) as endpoints using QSAR and chemical read-across approaches. The QSAR models were developed by strictly obeying the OECD guidelines and were found to be reliable, predictive, accurate, and robust. From the selected features in the developed models, we have found that an increase in lipophilicity and saturation, the presence of electrophilic or electronegative or heavy atoms, the presence of sulphur, amine, and their related functionality, an increase in mean atomic polarizability, and higher number of (thio-) carbamates (aromatic) groups are responsible for chronic toxicity. Therefore, this information might be useful for the development of environmentally friendly and safer chemicals and data-gap filling as well as reducing the use of identified toxic chemicals which have chronic toxic effects on aquatic ecosystems. Approved classes of drugs from DrugBank databases and diverse groups of chemicals from the Chemical and Product Categories (CPDat) database were also assessed through the developed models.


Asunto(s)
Daphnia magna , Contaminantes Químicos del Agua , Animales , Relación Estructura-Actividad Cuantitativa , Ecosistema , Daphnia , Contaminantes Químicos del Agua/toxicidad
3.
Mol Divers ; 25(1): 625-659, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32880078

RESUMEN

After the 1918 Spanish Flu pandemic caused by the H1N1 virus, the recent coronavirus disease 2019 (COVID-19) brought us to the time of serious global health catastrophe. Although no proven therapies are identified yet which can offer a definitive treatment of the COVID-19, a series of antiviral, antibacterial, antiparasitic, immunosuppressant drugs have shown clinical benefits based on repurposing theory. However, these studies are made on small number of patients, and, in majority of the cases, have been carried out as nonrandomized trials. As society is running against the time to combat the COVID-19, we present here a comprehensive review dealing with up-to-date information of therapeutics or drug regimens being utilized by physicians to treat COVID-19 patients along with in-depth discussion of mechanism of action of these drugs and their targets. Ongoing vaccine trials, monoclonal antibodies therapy and convalescent plasma treatment are also discussed. Keeping in mind that computational approaches can offer a significant insight to repurposing based drug discovery, an exhaustive discussion of computational modeling studies is performed which can assist target-specific drug discovery.


Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/efectos de los fármacos , Animales , COVID-19/virología , Biología Computacional/métodos , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , Humanos , Pandemias/prevención & control
4.
Xenobiotica ; 51(6): 625-635, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33539218

RESUMEN

CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using in-silico, in-vitro and in-vivo approaches.Results of in-vitro CYP2E1 inhibitory studies using CYP2E1-mediated chlorzoxazone 6-hydroxylation in human liver microsomes showed that glabridin have the highest potential than fisetin, epicatechin, nobiletin, and chrysin to inhibit CYP2E1 enzyme. Mechanistic investigations indicate that glabridin is a competitive CYP2E1 inhibitor. Molecular docking study results demonstrate that glabridin strongly interacted with the active site of human CYP2E1 enzyme. Pharmacokinetics of a CYP2E1 substrate in mice model indicates a significant alteration of chlorzoxazone and 6-hydroxychlorzoxazone plasma levels in the presence of glabridin. Further studies are needed to confirm the results at clinical level.Overall, glabridin is found to be a potential CYP2E1 inhibitor.


Asunto(s)
Citocromo P-450 CYP2E1 , Isoflavonas , Clorzoxazona , Isoflavonas/farmacología , Microsomas Hepáticos , Simulación del Acoplamiento Molecular , Fenoles
5.
Ecotoxicol Environ Saf ; 190: 110067, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31855788

RESUMEN

Earthworm provides sustainability towards the agroecosystem which can be degraded day by day by the extensive use of pesticides (e.g., fungicides, insecticides and herbicides). The present study attempts to develop a predictive quantitative structure-activity relationship (QSAR) model for toxicity of pesticides to earthworm in order to give a suitable guidance for designing new analogues with lower toxicity by exploring the important chemical features which are required to develop safer alternatives. The QSAR model was developed by using the negative logarithm of lethal concentration (pLC50) values of pesticides towards earthworm. We have used various 2D descriptors along with extended topochemical atom (ETA) indices as independent variables for the development of the model. The developed partial least squares (PLS) model was subjected to statistical validation tests proving that the model is statistically reliable and robust (R2 = 0.765, Q2 = 0.614, Q2F1 = 0.734, Q2F2 = 0.713). The contributing descriptors in the model suggested that the pesticides may affect the earthworm nucleic acid through various physicochemical interactions including hydrophobicity, hydrogen bonding, electron donor acceptor complex formation, π-π stacking interaction and charge transfer complex formation.


Asunto(s)
Oligoquetos/efectos de los fármacos , Plaguicidas/toxicidad , Animales , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Análisis de los Mínimos Cuadrados , Plaguicidas/química , Relación Estructura-Actividad Cuantitativa
6.
Pulm Pharmacol Ther ; 48: 151-160, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29174840

RESUMEN

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 µM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.


Asunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Nitrofuranos/uso terapéutico , Piperazinas/uso terapéutico , Tuberculosis/tratamiento farmacológico , Administración Oral , Animales , Antituberculosos/administración & dosificación , Antituberculosos/farmacología , Antituberculosos/toxicidad , Disponibilidad Biológica , Simulación por Computador , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Femenino , Células Hep G2 , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Nitrofuranos/administración & dosificación , Nitrofuranos/farmacología , Nitrofuranos/toxicidad , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piperazinas/toxicidad , Ratas , Pruebas de Toxicidad Aguda
7.
Sci Total Environ ; 954: 176175, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39270868

RESUMEN

The excessive use of pesticides (an important group of chemicals) in the agricultural as well as public sectors raises a health concern. Pesticides affect humans and other living organisms via the food chain. Therefore, it is very necessary to calculate the dissipation half-life of pesticides in plants. Experimental prediction of pesticide dissipation half-lives requires complex environmental conditions, high cost, and a long time. Thus, in-silico half-life predictions are suitable and the best alternative. Herein, a total of six PLS (partial least squares) models namely, M1 (overall), M2 (fruit), M3 (plant interior), M4 (leaf), M5 (plant surface), and M6 (whole plant) alongside two MLR (multiple linear regression) models i.e. M7 (fruit surface) and model M8 (straw) were generated using dissipation half-lives (log10(T1/2)) of pesticides in plants and their different parts. Models were constructed in strict accordance with the guidelines outlined by the Organization for Economic Co-operation and Development (OECD) and extensively validated using globally accepted validation metrics (determination coefficient (R2) = 0.610-0.795, leave-one-out (LOO) cross-validated correlation coefficient (Q2LOO) = 0.520-0.660, MAE-FITTED TRAIN (mean absolute error fitted train) = 0.119-0.148, MAE-LOOTRAIN = 0.132-0.177, predictive R2 or Q2F1 = 0.538-0.567, Q2F2 = 0.500-0.565, MAETEST = 0.122-0.232), confirming their accuracy, reliability, predictivity, and robustness. Lipophilicity, the presence of a cyclomatic ring, suphur, aromatic amine fragments, and chlorine atom fragments are responsible (+ve contribution) for high dissipation half-lives of pesticides in plants. In contrast, hydrophilicity, pyrazine fragments, and rotatable bonds reduce (-ve negative contribution) the dissipation half-lives of pesticides in plants. To address the real-world applicability, the models were employed to screen the PPDB (Pesticide Properties Database) database, which revealed the top 10 pesticides with the highest log(T1/2) in the whole plant and respective parts of the plant body. The present work will aid in developing safer and novel pesticides, regulatory risk assessment, various risk assessments for the sustenance of public health, screening of databases, and data-gap filling.

8.
Environ Sci Process Impacts ; 26(5): 870-881, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38652036

RESUMEN

Direct or indirect consumption of pesticides and their related products by humans and other living organisms without safe dosing may pose a health risk. The risk may arise after a short/long time which depends on the nature and amount of chemicals consumed. Therefore, the maximum acceptable daily intake of chemicals must be calculated to prevent these risks. In the present work, regression-based quantitative structure-activity relationship (QSAR) models were developed using 39 pesticides with maximum acceptable daily intake (MADI) for humans as the endpoint. From the statistical results (R2 = 0.674-0.712, QLOO2 = 0.553-0.580, Q(F1)2 = 0.544-0.611, and Q(F2)2 = 0.531-0.599), it can be inferred that the developed models were robust, reliable, reproducible, accurate, and predictive. Intelligent Consensus Prediction (ICP) was employed to improve the external predictivity (Q(F1)2 =0.579-0.657 and Q(F2)2 = 0.563-0.647) of the models. Some of the chemical markers responsible for toxicity enhancement are the presence of unsaturated bonds, lipophilicity, presence of C< (double bond-single bond-single bonded carbon), and the presence of sulphur and phosphate bonds at the topological distances 1 and 6, while the presence of hydrophilic groups and short chain fragments reduces the toxicity. The Pesticide Properties Database (PPDB) (1694 pesticides) was also screened with the developed models. Hence, this research work will be helpful for the toxicity assessment of pesticides before their synthesis, the development of eco-friendly and safer pesticides, and data-gap filling reducing the time, cost, and animal experimentation. Thus, this study might hold promise for future potential MADI assessment of pesticides and provide a meaningful contribution to the field of risk assessment.


Asunto(s)
Plaguicidas , Relación Estructura-Actividad Cuantitativa , Plaguicidas/análisis , Plaguicidas/toxicidad , Humanos , Medición de Riesgo/métodos , Contaminantes Ambientales/análisis
9.
Aquat Toxicol ; 273: 106985, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38875952

RESUMEN

In the modern era, chemicals and their products have been used everywhere like agriculture, healthcare, food, cosmetics, pharmaceuticals, household products, clothing industry, etc. These chemicals find their way to reach the aquatic ecosystem (directly/indirectly) and cause severe chronic and prolonged toxic effects to aquatic species which is also then translated to human beings. Prolonged and chronic toxicity data of many chemicals that are used daily is not available due to high experimentation testing costs, time investment, and the requirement of a large number of animal sacrifices. Thus, in silico approaches (e.g., QSAR (quantitative structure-activity relationship)) are the best alternative for chronic and prolonged toxicity predictions. The present work offers multi-endpoint (five endpoints: chronic_LOEC, prolonged_14D_LC50, prolonged_14D_NOEC, prolonged_21D_LC50, prolonged_21D_NOEC) QSAR models for addressing the prolonged and chronic aquatic toxicity of chemicals toward fish (O. latipes). The statistical results (R2 =0.738-0.869, QLOO2 =0.712-0.831, Q(F1)2 =0.618-0.731) of the developed models show that they were robust, reliable, reproducible, accurate, and predictive. Some of the features that are responsible for prolonged and chronic toxicity of chemicals towards O. latipes are as follows: the presence of substituted benzene, hydrophobicity, unsaturation, electronegativity, the presence of long-chain fragments, the presence of a greater number of atoms at conjugation, and the presence of halogen atoms. On the other hand, hydrophilicity and graph density descriptors retard the aquatic chronic and prolonged toxicity of chemicals toward O. latipes. The PPDB (pesticide properties database) and experimental and investigational classes of drugs from the DrugBank database were also screened using the developed model. Thus, these multi-endpoint models will be helpful for data-gap filling and provide a broad range of applicability. Therefore, this research will aid in the in silico QSAR (quantitative structure-activity relationship) prediction (non-animal testing) of the prolonged and chronic toxicity of untested and new toxic chemicals/drugs/pesticides, design and development of eco-friendly, novel, and safer chemicals, and help to protect the aquatic ecosystem from exposure to toxic and hazardous chemicals.


Asunto(s)
Ecosistema , Oryzias , Relación Estructura-Actividad Cuantitativa , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/toxicidad
10.
J Hazard Mater ; 476: 135087, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38964042

RESUMEN

Antiviral drugs are a cornerstone in the first line of antiviral therapy and their demand rises consistently with increments in viral infections and successive outbreaks. The drugs enter the waters due to improper disposal methods or via human excreta following their consumption; consequently, many of them are now classified as emerging pollutants. Hereby, we review the global dissemination of these medications throughout different water bodies and thoroughly investigate the associated risk they pose to the aquatic fauna, particularly our vertebrate relative fish, which has great economic and dietary importance and subsequently serves as a major doorway to the human exposome. Our risk assessment identifies eleven such drugs that presently pose high to moderate levels of risk to the fish. The antiviral drugs are likely to induce oxidative stress, alter the behaviour, affect different physiological processes and provoke various toxicological mechanisms. Many of the compounds exhibit elevated bioaccumulation potential, while, some have an increased tendency to leach through soil and contaminate the groundwater. Eight antiviral medications show a highly recalcitrant nature and would impact the aquatic life consistently in the long run and continue to influence the human exposome. Thereby, we call for urgent ecopharmacovigilance measures and modification of current water treatment methods.


Asunto(s)
Antivirales , Peces , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad , Medición de Riesgo , Humanos
11.
Int J Biol Macromol ; 269(Pt 1): 131784, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38697440

RESUMEN

GRK5 holds a pivotal role in cellular signaling pathways, with its overexpression in cardiomyocytes, neuronal cells, and tumor cells strongly associated with various chronic degenerative diseases, which highlights the urgent need for potential inhibitors. In this study, multiclass classification-based QSAR models were developed using diverse machine learning algorithms. These models were built from curated compounds with experimentally derived GRK5 inhibitory activity. Additionally, a pharmacophore model was constructed using active compounds from the dataset. Among the models, the SVM-based approach proved most effective and was initially used to screen DrugBank compounds within the applicability domain. Compounds showing significant GRK5 inhibitory potential underwent evaluation for key pharmacophoric features. Prospective compounds were subjected to molecular docking to assess binding affinity towards GRK5's key active site amino acid residues. Stability at the binding site was analyzed through 200 ns molecular dynamics simulations. MM-GBSA analysis quantified individual free energy components contributing to the total binding energy with respect to binding site residues. Metadynamics analysis, including PCA, FEL, and PDF, provided crucial insights into conformational changes of both apo and holo forms of GRK5 at defined energy states. The study identifies DB02844 (S-Adenosyl-1,8-Diamino-3-Thiooctane) and DB13155 (Esculin) as promising GRK5 inhibitors, warranting further in vitro and in vivo validation studies.


Asunto(s)
Quinasa 5 del Receptor Acoplado a Proteína-G , Aprendizaje Automático , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas , Relación Estructura-Actividad Cuantitativa , Quinasa 5 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Quinasa 5 del Receptor Acoplado a Proteína-G/química , Ligandos , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Termodinámica , Unión Proteica , Sitios de Unión , Enfermedad Crónica , Farmacóforo
12.
J Hazard Mater ; 471: 134326, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38636230

RESUMEN

The extensive use of various pesticides in the agriculture field badly affects both chickens and humans, primarily through residues in food products and environmental exposure. This study offers the first quantitative structure-toxicity relationship (QSTR) and quantitative read-across-structure toxicity relationship (q-RASTR) models encompassing the LOEL and NOEL endpoints for acute toxicity in chicken, a widely consumed protein. The study's significance lies in the direct link between chemical toxicity in chicken, human intake, and environmental damage. Both the QSTR and the similarity-based read-across algorithms are applied concurrently to improve the predictability of the models. The q-RASTR models were generated by combining read-across derived similarity and error-based parameters, alongside structural and physicochemical descriptors. Machine Learning approaches (SVM and RR) were also employed with the optimization of relevant hyperparameters based on the cross-validation approach, and the final test set prediction results were compared. The PLS-based q-RASTR models for NOEL and LOEL endpoints showed good statistical performance, as traced from the external validation metrics Q2F1: 0.762-0.844; Q2F2: 0.759-0.831 and MAEtest: 0.195-0.214. The developed models were further used to screen the Pesticide Properties DataBase (PPDB) for potential toxicants in chickens. Thus, established models can address eco-toxicological data gaps and development of novel and safe eco-friendly pesticides.


Asunto(s)
Pollos , Aprendizaje Automático , Plaguicidas , Relación Estructura-Actividad Cuantitativa , Animales , Plaguicidas/toxicidad , Salud Pública , Algoritmos
13.
J Comput Chem ; 34(12): 1071-82, 2013 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-23299630

RESUMEN

Quantitative structure-activity relationship (QSAR) techniques have found wide application in the fields of drug design, property modeling, and toxicity prediction of untested chemicals. A rigorous validation of the developed models plays the key role for their successful application in prediction for new compounds. The r(m)(2) metrics introduced by Roy et al. have been extensively used by different research groups for validation of regression-based QSAR models. This concept has been further advanced here with introduction of scaling of response data prior to computation of r(m)(2). Further, a web application (accessible from http://aptsoftware.co.in/rmsquare/ and http://203.200.173.43:8080/rmsquare/) for calculation of the r(m)(2) metrics has been introduced here. The present study reports that the web application can be easily used for computation of r(m)(2) metrics provided observed and QSAR-predicted data for a set of compounds are available. Further, scaling of response data is recommended prior to r(m)(2) calculation.


Asunto(s)
Diseño de Fármacos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Modelos Teóricos
14.
Chemosphere ; 335: 139066, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37257655

RESUMEN

The recent years have witnessed an upsurge of interest to assess the toxicity of organic chemicals exhibiting harmful impacts on the environment. In this investigation, we have developed regression-based quantitative structure-toxicity relationship (QSTR) models against three protozoan species (Entosiphon sulcantum, Uronema parduczi, and Chilomonas paramecium) using three sets of descriptor combinations such as ETA indices only, non-ETA descriptors only, and both ETA and non-ETA descriptors to examine the key structural features that determine the toxic properties of protozoa. The interspecies QSTR models (i-QSTRs) were also generated for efficient data gap-filling of toxicity databases. The statistical results of the validated models in terms of both internal and external validation metrics suggested that the models are statistically reliable and robust. Additionally, using these validated models, we screened the DrugBank database containing 11,300 pharmaceuticals for assessing the ecotoxicological properties. The features appearing in the models suggested that non-polar characteristics, electronegativity, hydrogen bonding, π-π, and hydrophobic interactions are responsible for chemical toxicity toward protozoan. The validated models may be utilized for the development of eco-friendly drugs & chemicals, data gap-filling of toxicity databases for regulatory purposes and research, as well as to decrease the use of toxic and hazardous chemicals in the environment.


Asunto(s)
Compuestos Orgánicos , Relación Estructura-Actividad Cuantitativa , Compuestos Orgánicos/toxicidad , Ecotoxicología , Sustancias Peligrosas , Interacciones Hidrofóbicas e Hidrofílicas
15.
Aquat Toxicol ; 257: 106429, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36842883

RESUMEN

Polychlorinated naphthalenes (PCNs) are produced from a variety of industrial sources, and they reach the aquatic ecosystems by the dry-wet deposition from the atmosphere and also by the drainage from the land surfaces. Then the PCNs can be transmitted through the food chain to humans and show toxic effects on different aquatic animals as well as humans. Considering this scenario, it is an obligatory task to explore the toxicity data of PCNs more deeply for the species of an aquatic ecosystem (green algae-Daphnia magna-fish), and to extrapolate those data for humans. But the toxicity data for different aquatic species are quite limited. The laboratory experimentations are complicated and ethically troublesome to fill toxicity data gaps; therefore, different in silico methods (e.g., QSAR, quantitative read-across predictions) are emerging as crucial ways to fill the data gaps and hazard assessments. In the present study, we developed individual toxicity models as well as interspecies models from the 75 PCN toxicity data against three aquatic species (green algae-Daphnia magna-fish) by employing easily interpretable 2D descriptors; these models were validated rigorously employing different globally accepted internal and external validation metrics. Then we interpreted the modelled descriptors mechanistically with the endpoint values for better understanding. And finally, we endeavored to improve the prediction quality in terms of external validation metrics by employing a novel quantitative read-across approach by pooling the descriptors from the developed individual QSAR models.


Asunto(s)
Ecosistema , Contaminantes Químicos del Agua , Animales , Humanos , Naftalenos/toxicidad , Relación Estructura-Actividad Cuantitativa , Contaminantes Químicos del Agua/toxicidad , Peces , Simulación por Computador
16.
Chem Biol Interact ; 380: 110524, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37146929

RESUMEN

CYP2C8 is a crucial CYP isoform responsible for the metabolism of xenobiotics and endogenous molecules. CYP2C8 converts arachidonic acid to epoxyeicosatrienoic acids (EETs) that cause cancer progression. Rottlerin possess significant anticancer actions. However, information on its CYP inhibitory action is lacking in the literature and therefore, we aimed to explore the same using in silico, in vitro, and in vivo approaches. Rottlerin showed highly potent and selective CYP2C8 inhibition (IC50 < 0.1 µM) compared to negligible inhibition (IC50 > 10 µM) for seven other experimental CYPs in human liver microsomes (HLM) (in vitro) using USFDA recommended index reactions. Mechanistic studies reveal that rottlerin could reversibly (mixed-type) block CYP2C8. Molecular docking (in silico) results indicate a strong interaction could occur between rottlerin and the active site of human CYP2C8. Rottlerin boosted the plasma exposure of repaglinide and paclitaxel (CYP2C8 substrates) by delaying their metabolism using the rat model (in vivo). Multiple-dose treatment of rottlerin with CYP2C8 substrates lowered the CYP2C8 protein expression and up-regulated & down-regulated the mRNA for CYP2C12 & CYP2C11 (rat homologs), respectively, in rat liver tissue. Rottlerin substantially hindered the EET formation in HLM. Overall results of rottlerin on CYP2C8 inhibition and EET formation insinuate further exploration for cancer therapy.


Asunto(s)
Sistema Enzimático del Citocromo P-450 , Neoplasias , Humanos , Ratas , Animales , Citocromo P-450 CYP2C8/metabolismo , Simulación del Acoplamiento Molecular , Sistema Enzimático del Citocromo P-450/metabolismo , Acetofenonas , Microsomas Hepáticos/metabolismo , Neoplasias/metabolismo
17.
Life Sci ; 317: 121467, 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36736764

RESUMEN

AIMS: This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations. MAIN METHODS: A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s). KEY FINDINGS: PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70). SIGNIFICANCE: The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Neoplasias Hepáticas/tratamiento farmacológico , Paclitaxel/farmacología , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral
18.
J Chem Inf Model ; 52(2): 396-408, 2012 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-22201416

RESUMEN

Quantitative structure-property relationship (QSPR) models used for prediction of property of untested chemicals can be utilized for prioritization plan of synthesis and experimental testing of new compounds. Validation of QSPR models plays a crucial role for judgment of the reliability of predictions of such models. In the QSPR literature, serious attention is now given to external validation for checking reliability of QSPR models, and predictive quality is in the most cases judged based on the quality of predictions of property of a single test set as reflected in one or more external validation metrics. Here, we have shown that a single QSPR model may show a variable degree of prediction quality as reflected in some variants of external validation metrics like Q²(F1), Q²(F2), Q²(F3), CCC, and r²(m) (all of which are differently modified forms of predicted variance, which theoretically may attain a maximum value of 1), depending on the test set composition and test set size. Thus, this report questions the appropriateness of the common practice of the "classic" approach of external validation based on a single test set and thereby derives a conclusion about predictive quality of a model on the basis of a particular validation metric. The present work further demonstrates that among the considered external validation metrics, r²(m) shows statistically significantly different numerical values from others among which CCC is the most optimistic or less stringent. Furthermore, at a given level of threshold value of acceptance for external validation metrics, r²(m) provides the most stringent criterion (especially with Δr²(m) at highest tolerated value of 0.2) of external validation, which may be adopted in the case of regulatory decision support processes.


Asunto(s)
Relación Estructura-Actividad Cuantitativa , Estudios de Validación como Asunto , Modelos Teóricos
19.
ACS Omega ; 7(23): 20321-20331, 2022 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-35721953

RESUMEN

Pinocembrin, a bioflavonoid, is extensively used in complementary/alternative medicine. It turns out as a promising candidate against neurodegenerative diseases because of its multifaceted pharmacological action toward neuroprotection. However, literature evidence is still lacking for its inhibitory action on CYP1A2, which is responsible for xenobiotic metabolism leading to the generation of toxic metabolites and bioactivation of procarcinogens. In the present study, our aim was to evaluate the CYP1A2 inhibitory potential of pinocembrin via in silico, in vitro, and in vivo investigations. From the results of in vitro studies, pinocembrin is found to be a potent and competitive inhibitor of CYP1A2. In vitro-in vivo extrapolation results indicate the potential of pinocembrin to interact with CYP1A2 substrate drugs clinically. Molecular docking-based in silico studies demonstrate the strong interaction of pinocembrin with human CYP1A2. In in vivo investigations using a rat model, pinocembrin displayed a marked alteration in the plasma exposure of CYP1A2 substrate drugs, namely, caffeine and tacrine. In conclusion, pinocembrin has a potent CYP1A2 inhibitory action to cause drug interactions, and further confirmatory study is warranted at the clinical level.

20.
ACS Omega ; 7(15): 13260-13269, 2022 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-35474783

RESUMEN

Myricetin, a bioflavonoid, is widely used as functional food/complementary medicine and has promising multifaceted pharmacological actions against therapeutically validated anticancer targets. On the other hand, CYP2C8 is not only crucial for alteration in the pharmacokinetics of drugs to cause drug interaction but also unequivocally important for the metabolism of endogenous substances like the formation of epoxyeicosatrienoic acids (EETs), which are considered as signaling molecules against hallmarks of cancer. However, there is hardly any information known to date about the effect of myricetin on CYP2C8 inhibition and, subsequently, the CYP2C8-mediated drug interaction potential of myricetin at the preclinical/clinical level. We aimed here to explore the CYP2C8 inhibitory potential of myricetin using in silico, in vitro, and in vivo investigations. In the in vitro study, myricetin showed a substantial effect on CYP2C8 inhibition in human liver microsomes using CYP2C8-catalyzed amodiaquine-N-deethylation as an index reaction. Considering the Lineweaver-Burk plot, the Dixon plot, and the higher α-value, myricetin is found to be a mixed type of CYP2C8 inhibitor. Moreover, in vitro-in vivo extrapolation data suggest that myricetin is likely to cause drug interaction at the hepatic level. The molecular docking study depicted a strong interaction between myricetin and the active site of the human CYP2C8 enzyme. Moreover, myricetin caused considerable elevation in the oral exposure of amodiaquine as a CYP2C8 substrate via a slowdown of amodiaquine clearance in the rat model. Overall, the potent action of myricetin on CYP2C8 inhibition indicates that there is a need for further exploration to avoid drug interaction-mediated precipitation of obvious adverse effects as well as to optimize anticancer therapy.

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