Computational evaluation of 1,2,3-triazole-based VEGFR-2 inhibitors: anti-angiogenesis potential and pharmacokinetic assessment.

The vascular endothelial growth factor (VEGF) and its cell surface receptor, as well as the human VEGFR-2 domain kinase, are some of the signaling pathways that have received the most attention in this field. This study aimed to identify novel molecules as VEGFR-2 inhibitors using 3D-QSAR modeling based on 1,2,3-triazole. Docking studies and dynamic simulations were performed to analyze novel interactions with the inhibitors and validate the molecular docking, dynamic simulations, and ADMET analyses. The optimized CoMSIA/SEH model showed good statistical results, and molecular docking and molecular dynamics simulations demonstrated stability of M3 ligand with the receptor and provided insight into ligand-receptor interactions. The newly developed compounds performed well in ADMET evaluations and showed promising results using Lipinski's rule of five, suggesting that the molecule M3 could be a useful anti-angiogenesis agent. In conclusion, this study provides insights into the structure-activity relationship of VEGFR-2 inhibitors and identifies M3 as a potential new anti-angiogenesis drug. The methodology used in this study can be applied to other similar drug targets to discover new and potent inhibitors.Communicated by Ramaswamy H. Sarma.

Exploring azomethine ylides reactivity with acrolein through cycloaddition reaction and computational antiviral activity assessment against hepatitis C virus.

CONTEXT: The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor. METHODS: Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.

3D-QSAR, molecular docking, simulation dynamic and ADMET studies on new quinolines derivatives against colorectal carcinoma activity.

Cancer is the uncontrolled spread of abnormal cells that results in abnormal tissue growth in the affected organ. One of the most important organs is exposed to the growth of colon cancer cells, which start in the large intestine (colon) or the rectum. Several therapeutic protocols were used to treat different kinds of cancer. Recently, several studies have targeted tubulin and microtubules due to their remarkable prefoliation. Also, recent research shows that quinoline compounds have significant efficacy against human colorectal cancer. So, the present work investigated the potential of thirty quinoline compounds as tubulin inhibitors using computational methods. A 3D-QSAR approach using two contours (CoMFA and CoMSIA), molecular docking simulation to determine the binding type of the complexes (ligand-receptor), molecular dynamics simulation and identifying pharmacokinetic characteristics were used to design molecules. For all compounds designed (T1-5), molecular docking was used to compare the stability by type of binding. The ADMET has been utilized for molecules with good stability in molecular docking (T1-3); these compounds have good medicinal characteristics. Furthermore, a molecular dynamics simulation (MD) at 100 ns was performed to confirm the stability of the T1-3 compounds; the molecules (T1-3) remained the most stable throughout the simulation. The compounds T1, T2 and T3 are the best-designed drugs for colorectal carcinoma treatments.Communicated by Ramaswamy H. Sarma.

In silico identification of 1,2,4-triazoles as potential Candida Albicans inhibitors using 3D-QSAR, molecular docking, molecular dynamics simulations, and ADMET profiling.

Fluconazole and Voriconazole are individual antifungal inhibitors broadly adopted for treating fungal infections, including Candida Albicans. Unfortunately, these medicines clinically used have significant side effects. Consequently, the improvement of safer and better therapy became more indispensable. In this study, a set of 27 1,2,4-triazole compounds have been tested as potential Candida Albicans inhibitors by using different theoretical methods. The created comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour maps significantly impacted the development of novel Candida Albicans inhibitors with valuable activities. The mode of interactions between the 1,2,4-triazole inhibitors and the targeted receptor was studied by molecular docking simulation. The proposed new molecule P1 showed satisfied stability in the active pocket of the targeted receptor compared to the more active molecule in the dataset compared to Fluconazole medication. Meanwhile, the binding energy obtained by molecular docking for molecule P1 is - 9.3 kcal/mol compared with - 6.7 kcal/mol for Fluconazole medication. Also, MM/GBSA value obtained by molecular dynamics simulations at 100 ns for molecule P1 is - 33.34 kcal/mol compared with - 15.85 kcal/mol for Fluconazole medication. In addition, molecule P1 showed good oral bioavailability and was non-toxic according to ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the results indicated compound P1 might be a future inhibitor of Candida Albicans infection.

Novel Eubacterium rectale inhibitor from Coriandrum sativum L. for possible prevention of colorectal cancer: a computational approach.

This research aims to screen out the effective bioactive compounds from Coriander (Coriandrum sativum L.), which may be novel potential inhibitors of Eubacterium rectale for the prevention of colorectal cancer (CRC). A series of 8 coriander-derived chemical compounds previously assessed for their anti-inflammatory, antioxidant, and antidiabetic activities were tested against Carbohydrate ABC transporter substrate-binding protein and compared to the standard inhibitor Acarbose, to support their use as novel Eubacterium rectale inhibitors. Herein, these derivatives were submitted to a thorough analysis of docking studies, in which detailed interactions of the selected phytocompounds with carbohydrate ABC transporter substrate-binding protein were revealed. Molecular docking analysis recommends Rutin, Gallocatechin, and Epigallocatechin as the most potential Eubacterium rectale inhibitors among the eight selected phytochemical compounds. Subsequently, the stability of the three selected phytochemical complexes was checked using molecular dynamics (MD) simulation at 100 ns and Molecular Mechanics combined with Poisson-Boltzmann Surface Area (MM-PBSA). The results show quite good stability for Rutin and Gallocatechin. In silico ADMET prediction was performed on the selected compounds, and the findings revealed a reasonably good ADMET profile for both Rutin and Gallocatechin. The current findings predict that Gallocatechin could be a better CRC preventive natural compound, and, further in vitro, in vivo and clinical studies may confirm its therapeutic potential.Communicated by Ramaswamy H. Sarma.

Computational approach investigation bioactive molecules from Saussurea Costus plant as SARS-CoV-2 main protease inhibitors using reverse docking, molecular dynamics simulation, and pharmacokinetic ADMET parameters.

SARS-COV-2 virus causes (COVID-19) disease; it has become a global pandemic since 2019 and has negatively affected all aspects of human life. Scientists have made great efforts to find a reliable cure, vaccine, or treatment for this emerging disease. Efforts have been directed towards using medicinal plants as alternative medicines, as the active chemical compounds in them have been discovered as potential antiviral or anti-inflammatory agents. In this research, the potential of Saussurea costus (S. Costus) or QUST Al Hindi chemical consistent as potential antiviral agents was investigated by using computational methods such as Reverse Docking, ADMET, and Molecular Dynamics with different proteases COVID-19 such as PDB: 2GZ9; 6LU7; 7AOL, 6Y2E, 6Y84. The results of Reverse Docking the complex between 6LU7 proteases and Cynaropicrin compound being the best complex, as the same result, is achieved by molecular dynamics. Also, the toxicity testing result from ADMET method proved that the complex is the least toxic and the safest possible drug. In addition, 6LU7-Cynaropicrin complex obeyed Lipinski rule; it formed ≤5 H-bond donors and ≤10 H bond acceptors, MW < 500 Daltons, and octanol/water partition coefficient <5.

Chemical Composition of Cactus Pear Seed Oil: phenolics identification and antioxidant activity.

Objectives: The chemical composition of cactus pear seed oil (Opuntia ficus-indica [L.] Mill.) was analyzed in terms of its fatty acid composition, tocopherol content, phenolic identification, and the oil's phenolic-rich fraction antioxidant power was determined. Methods: Fatty acid profiling was performed by gas chromatography coupled to an FI detector. Tocopherols and phenolic compounds were analyzed by LC-FLD/UV, and the oil's phenolic-rich fraction antioxidant power was determined by phosphomolybdenum, DPPH assay and ß-carotene bleaching test. Results: Fatty acid composition was marked by a high unsaturation level (83.22 ± 0.34%). The predominant fatty acid was linoleic acid (66.79 ± 0.78%), followed by oleic acid (15.16 ± 0.42%) and palmitic acid (12.70 ± 0.03%). The main tocopherol was γ-tocopherol (172.59 ± 7.59 mg/kg. In addition, Tyrosol, vanillic acid, vanillin, ferulic acid, pinoresinol, and cinnamic acid were identified as phenolic compounds in the analyzed seed oil. Moreover, the oil's phenolics-rich fraction showed a significant total antioxidant activity, scavenged DPPH up to 97.85%, and effectively protected ß-carotene against bleaching (97.56%). Conclusion: The results support the potential use of cactus pear seed oil as a functional food.

Molecular docking, molecular dynamics simulation, and ADMET analysis of levamisole derivatives against the SARS-CoV-2 main protease (MPro).

Introduction: The new species of coronaviruses (CoVs), SARS-CoV-2, was reported as responsible for an outbreak of respiratory disease. Scientists and researchers are endeavoring to develop new approaches for the effective treatment against of the COVID-19 disease. There are no finally targeted antiviral agents able to inhibit the SARS-CoV-2 at present. Therefore, it is of interest to investigate the potential uses of levamisole derivatives, which are reported to be antiviral agents targeting the influenza virus. Methods: In the present study, 12 selected levamisole derivatives containing imidazo[2,1-b]thiazole were subjected to molecular docking in order to explore the binding mechanisms between these derivatives and the SARS-CoV-2 Mpro (PDB: 7BQY). The levamisole derivatives were evaluated for in silico ADMET properties for wet-lab applicability. Further, the stability of the best-docked complex was checked using molecular dynamics (MD) simulation at 20 ns. Results: Levamisole derivatives and especially molecule N°6 showed more promising docking results, presenting favorable binding interactions as well as better docking energy compared to chloroquine and mefloquine. The results of ADMET prediction and MD simulation support the potential of the molecule N°6 to be further developed as a novel inhibitor able to stop the newly emerged SARS-CoV-2. Conclusion: This research provided an effective first line in the rapid discovery of drug leads against the novel CoV (SARS-CoV-2).

Identification of novel acetylcholinesterase inhibitors through 3D-QSAR, molecular docking, and molecular dynamics simulation targeting Alzheimer's disease.

Acetylcholinesterase (AChE) is a potential target for the development of small molecules as inhibitors for the therapy of Alzheimer's disease (AD). To design highly active acetylcholinesterase inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach was performed on a series of N-benzylpyrrolidine derivatives previously evaluated for acetylcholinesterase inhibitory activity. The developed two models, CoMFA and CoMSIA, were statistically validated, and good predictability was achieved for both models. The information generated from 3D-QSAR contour maps may provide a better understanding of the structural features required for acetylcholinesterase inhibition and help to design new potential anti-acetylcholinesterase molecules. Consequently, six novel acetylcholinesterase inhibitors were designed, among which compound A1 with the highest predicted activity was subjected to detailed molecular docking and compared to the most active compound. Extra-precision molecular dynamics (MD) simulation of 50 ns and binding free energy calculations using MM-GBSA were performed for the selected compounds to validate the stability. These results may afford important structural insights needed to identify novel acetylcholinesterase inhibitors and other promising strategies in drug discovery.

Integrated 3D-QSAR, molecular docking, and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors.

Alzheimer's disease (AD) is a multifactorial and polygenic disease. It is the most prevalent reason for dementia in the aging population. A dataset of twenty-six 1,2,3-triazole-based derivatives previously synthetized and evaluated for acetylcholinesterase inhibitory activity were subjected to the three-dimensional quantitative structure-activity relationship (3D-QSAR) study. Good predictability was achieved for comparative molecular field analysis (CoMFA) (Q2 = 0.604, R2 = 0.863, rext 2 = 0.701) and comparative molecular similarity indices analysis (CoMSIA) (Q2 = 0.606, R2 = 0.854, rext 2 = 0.647). The molecular features characteristics provided by the 3D-QSAR contour plots were quite useful for designing and improving the activity of acetylcholinesterase of this class. Based on these findings, a new series of 1,2,3-triazole based derivatives were designed, among which compound A1 with the highest predictive activity was subjected to detailed molecular docking and compared to the most active compound. The selected compounds were further subjected to 20 ns molecular dynamics (MD) simulations to study the comparative conformation dynamics of the protein after ligand binding, revealing promising results for the designed molecule. Therefore, this study could provide worthy guidance for further experimental analysis of highly effective acetylcholinesterase inhibitors.

Prediction of potential inhibitors of SARS-CoV-2 using 3D-QSAR, molecular docking modeling and ADMET properties.

Coronavirus (COVID-19), an enveloped RNA virus, primarily affects human beings. It has been deemed by the World Health Organization (WHO) as a pandemic. For this reason, COVID-19 has become one of the most lethal viruses which the modern world has ever witnessed although some established pharmaceutical companies allege that they have come up with a remedy for COVID-19. To that end, a set of carboxamides sulfonamide derivatives has been under study using 3D-QSAR approach. CoMFA and CoMSIA are one of the most cardinal techniques used in molecular modeling to mold a worthwhile 3D-QSAR model. The expected predictability has been achieved using the CoMFA model (Q2 = 0.579; R2 = 0.989; R2test = 0.791) and the CoMSIA model (Q2 = 0.542; R2 = 0.975; R2test = 0.964). In a similar vein, the contour maps extracted from both CoMFA and CoMSIA models provide much useful information to determine the structural requirements impacting the activity; subsequently, these contour maps pave the way for proposing 8 compounds with important predicted activities. The molecular surflex-docking simulation has been adopted to scrutinize the interactions existing between potentially and used antimalarial molecule on a large scale, called Chloroquine (CQ) and the proposed carboxamides sulfonamide analogs with COVID-19 main protease (PDB: 6LU7). The outcomes of the molecular docking point out that the new molecule P1 has high stability in the active site of COVID-19 and an efficient binding affinity (total scoring) in relation with the Chloroquine. Last of all, the newly designed carboxamides sulfonamide molecules have been evaluated for their oral bioavailability and toxicity, the results point out that these scaffolds have cardinal ADMET properties and can be granted as reliable inhibitors against COVID-19.

Chenopodium ambrosioides induces an endothelium-dependent relaxation of rat isolated aorta / 中西医结合学报

OBJECTIVE@#This study aims to evaluate the vasodilatory effect of Chenopodium ambrosioides on the isolated rat aorta, and to explore its mechanism of action.@*METHODS@#The vasorelaxant effect and the mode of action of various extracts from the leaves of C. ambrosioides were evaluated on thoracic aortic rings isolated from Wistar rats. In addition, ethyl acetate and methanol fractions were analyzed, using thin-layer chromatography and high-performance liquid chromatography techniques, for their polyphenolic content.@*RESULTS@#The various active extracts of C. ambrosioides at four concentrations (10, 10, 10 and 1 mg/mL) relaxed the contraction elicited by phenylephrine, in a concentration-dependent manner. This effect seems to be endothelium-dependent, since the vasodilatory effect was entirely absent in denuded aortic rings. The vasorelaxant effect of the methanol fraction (MF) of C. ambrosioides at 1 mg/mL was also inhibited by atropine and tetraethylammonium. This effect remained unchanged by Nω-nitro-l-arginine methyl ester hydrochloride and glibenclamide. The preliminary phytochemical analysis showed that the leaves of C. ambrosioides are rich in phenolic and flavonoid derivatives.@*CONCLUSION@#These results suggest that the MF of C. ambrosioides produces an endothelium-dependent relaxation of the isolated rat aorta, which is thought to be mediated mainly through stimulation of the muscarinic receptors, and probably involving the opening of Ca-activated potassium channels.

Antidiabetic effect of Opuntia dillenii seed oil on streptozotocin-induced diabetic rats

Objective: To assess the antidiabetic effect of Opuntia dillenii seed oil on rats with diabetes mellitus. Methods: A rat diabetes model was established by intraperitoneal injection of rats with 50 mg/kg streptozotocin. Thirty albino Wistar rats were divided into five groups: the diabetic control group and normal control group were treated only with distilled water, two diabetic groups received 1 and 2 mL/kg of oil per day, respectively, for 30 days and one diabetic group received 2 mg/kg of glibenclamide. In addition, blood glucose was determined weekly. Body weight, average daily food, water intake and urinary volume of each animal were determined before and after the treatment period. After the treatment period, hepatic glycogen was determined using the anthrone reagent, and glycosuria, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, urea, creatinine and uric acid were estimated using common clinical diagnostic kits. Results: Oral intake of the oil at 1 and 2 mL/kg for the diabetic animals significantly diminished blood glucose, glycosuria, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, urea, creatinine and uric acid, accompanied by a noticeable elevation in the amount of hepatic glycogen in comparison with the diabetic control group. Similarly, Opuntia dillenii seed oil significantly increased the food intake and decreased the urinary volume per day in treated rats of the same groups in comparison with the period before the treatment intervention and attenuated body weight loss in the diabetic rats. Moreover, this effect of the oil was dose dependent. On the other hand, the oil did not affect their need for water. Conclusions: The results show that Opuntia dillenii seed oil has a very important antidiabetic effect on streptozotocin-induced diabetic rats. Hence, we suggest it as a preventive control of diabetes mellitus.

Hepatoprotective effect of Opuntia dillenii seed oil on CCl

Objective: To investigate the hepatoprotective effect of Opuntia dillenii seed oil (ODSO) on CCl

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study.

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).

Evaluation of protective effect of cactus pear seed oil (Opuntia ficus-indica L. MILL.) against alloxan-induced diabetes in mice.

OBJECTIVE: To evaluate the in vitro antioxidant power of cactus pear seed oil [Opuntia ficus-indica L. MILL. (CPSO)] and its protective effect against chemically induced diabetes mellitus in mice. METHODS: The in vitro antioxidant effect of CPSO was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. The preventive effect was conducted on Swiss albino mice treated with CPSO (2 mL/kg, per os), before and after a single intraperitoneal alloxan administration (100 mg/kg). Survival rate, body weight and fasting blood glucose were measured and histopathological analysis of pancreas was performed to evaluate alloxan-induced tissue injuries. RESULTS: CPSO exhibited an antioxidant effect in DPPH scavenging assay. Moreover, the administration of CPSO (2 mL/kg) significantly attenuated alloxan-induced death and hyperglycemia (P < 0.001) in treated mice. Morphometric study of pancreas revealed that CPSO significantly protected islets of langerhans against alloxan induced-tissue alterations. CONCLUSIONS: Based on theses results, CPSO can prevente alloxan-induced-diabetes by quenching free radicals produced by alloxan and inhibiting tissue injuries in pancreatic ß-cells.

Direct conversion of multilayer molybdenum trioxide to nanorods as multifunctional electrodes in lithium-ion batteries.

In this study we prepared molybdenum trioxide (MoO3) nanorods having average lengths of 0.5-1.5 µm and widths of approximately 100-200 nm through a one-step mechanical break-down process involving favorable fracturing along the crystal direction. We controlled the dimensions of the as-prepared nanorods by applying various imposing times (15-90 min). The nanorods prepared over a reaction time of 90 min were, on average, much shorter and narrower relative to those obtained over 30 min. Evaluations of lithium-ion storage properties revealed that the electrochemical performance of these nanorods was much better than that of bulk materials. As cathodes, the nanorods could deliver a high specific capacity (>315 mA h g(-1)) with losses of less than 2% in the first cycle at a rate of 30 mA g(-1); as anodes, the specific capacity was 800 mA h g(-1) at a rate of 50 mA g(-1). Relative to α-MoO3 microparticles, these nanorods displayed significantly enhanced lithium-ion storage properties with higher reversible capacities and better rate performance, presumably because their much shorter diffusion lengths and higher specific surface areas allowed more-efficient insertion/deinsertion of lithium ions during the charge/discharge process. Accordingly, enhanced physical and/or chemical properties can be obtained through appropriate nanostructuring of materials.

Arriving safely and avoiding a puncture: use of a Radi PressureWire to cross an ATS prosthetic aortic valve for direct measurement of left ventricular pressure.

The direct measurement of left ventricular pressure in the presence of a mechanical aortic valve is a technical challenge for the interventional cardiologist. Direct recording, which is rarely performed, becomes necessary when other imaging methods have failed to evaluate prosthetic valve stenosis or restrictive physiology. Left ventricular pressure has typically been measured after transseptal or direct left ventricular apical puncture.In recent years, investigators have used the 0.014-in coronary Radi PressureWire™ (St. Jude Medical, Inc.; St. Paul, Minn) to cross the St. Jude bileaflet prosthetic aortic valve without the need for puncture. Although another bileaflet aortic valve, the ATS Open Pivot® (ATS Medical, Inc.; Minneapolis, Minn), has an overall design similar to that of the St. Jude valve, the ATS valve has an open-pivot hinge, which has the potential for wire entrapment.Herein, we describe how we successfully measured left ventricular pressure by crossing an ATS Open Pivot prosthetic valve with a Radi PressureWire, in a 60-year-old man in whom pericardial constriction was suspected. The straightforward, uncomplicated procedure enabled confirmation of the diagnosis. We believe that further investigation of this technique is warranted.