Smilax zeylanica is a medicinal plant native to Southeast Asia that has been used for centuries to treat a variety of ailments, including hyperlipidemia. However, the mechanisms underlying its antilipidemic effects are not fully understood. In this study, we performed metabolomic profiling of S. zeylanica roots extracts and screened for potential antilipidemic compounds using in vitro and in silico methods. Metabolomic analysis using spectral and Chromatographic techniques such as GSMS and HPLC revealed that S. zeylanica roots contain a variety of metabolites, including flavonoids, phenolic acids namely gallic acid, chlorogenic acid, Quercetin and several other potent phytoconstituents. In vitro pancreatic lipase assays, HMGCoA reductase assay showed that S. zeylanica root extract significantly showed inhibitory potential at par with the standard drug orlistat and atorvastatin respectively. Molecular docking studies showed that several of the metabolites identified in S. zeylanica roots, including quercetin, kaempferol, and gallic acid, etc bind to the HMG-CoA reductase enzyme, a key enzyme in cholesterol biosynthesis. These findings suggest that S. zeylanica may exert its antilipidemic effects by inhibiting HMG-CoA reductase activity. Overall, this study provides new insights into the metabolomic profile of S. zeylanica and its potential antilipidemic activity. Further studies are needed to elucidate the specific mechanisms underlying its antilipidemic effects and to confirm its safety and efficacy profiles.

[Background/Aims] Diseases resulting from inadequate elimination of oxidative stress due to aging and the entry of nanoparticles such as particle matters and plastics into the body have been on the rise in recent years. The importance of glutathione as a method of eliminating oxidative stress and nanoparticles has been recognized. The use of foods and nutrients has gained attention as a way to increase or support the maintenance of optimal levels of glutathione in the body. In the present study, the effects of increasing glutathione production in the liver of jumbo leek bulb powder were examined using samples that were heat-treated after rapid and synchronized dormancy-breaking to promote phase transition of the contents.

[Results] The heat- and freeze-dried samples without rapid and synchronized dormancy-breaking (untreated) showed a 9-fold increase in total glutathione compared to the control. In contrast, the rapid and synchronized dormancy-breaking sample showed an even greater increase, approximately 35-fold over the control and 4-fold over the untreated sample, indicating a significantly higher increase. This suggests that ingestion of rapid and synchronized dormancy-breaking jumbo leek bulb powder will promote the alleviation of oxidative stress in the body and the removal of nanoparticles due to the increase in the amount of glutathione in the liver. Therefore, it is expected to prevent or improve (anti-aging) cerebral infarction, cancer, wrinkles, and blemishes caused by these factors, as well as to prevent obesity and diabetes, as reported last year.

TRPA1 is a transient receptor potential (TRP) cation channel superfamily member. These receptors have a role in many processes like inflammation, metabolism, sensation, and tumorigenesis. Previous studies showed that TRPA1 can form adducts with reactive aldehydes, which trigger the release of pro-inflammatory mediators. The reactive aldehydes can be exogenous, from alcohol or tobacco consumption, or can result from lipid peroxidation under oxidative stress conditions.

We show in our preliminary studies, using Ca²⁺ microfluorimetry, that 4-hydroxynonenal (4-HNE) stimulates Ca²⁺ uptake by TRPA1. 4-HNE is an endogenous aldehyde with an essential role in both physiological and pathological processes. To further elucidate this effect, we used molecular docking methods to investigate the interaction of human TRPA1 with 4-HNE.

Initially, we confirmed the affinity of 4-HNE for the expected binding site represented by the cysteine pocket, including Cys621, the main residue involved in the binding of covalent ligands. Covalent docking simulations between Cys621 and HNE were performed to obtain possible adduct conformations. The best poses will be analyzed by molecular dynamics to understand the mechanism by which HNE modulates TRPA1 activity. The obtained data would provide insight into possible future pharmacological strategies for targeting the interaction between TRP channels and reactive aldehydes in pathologic conditions.

Heterocyclic chemistry plays a crucial role in drug design and the development of novel biologically active compounds. Many synthetic products with diverse pharmacological benefits feature heterocyclic structures, making them essential in the medicinal field.

One notable class of heterocycles is 4-hydroxyquinolin-2-one, which hold significant importance in medicinal chemistry. 4-hydroxyquinolin-2-ones find wide-ranging applications as therapeutic agents, exhibiting antibacterial, anticancer, antiproliferative, analgesic, antiallergenic, and antitubercular activities. They have also been identified as antagonists of the cannabinoid type 2 receptor and modulators of glycogen synthase kinase GSK-3.

To continue our research into the synthesis of new bioactive agents; we synthesized and characterized a derivative of 4-hydroxyquinolin-2-one. This synthesis involved a two-step process: initially, we produced an enaminone by condensing cyclohexylamine with dimedone, employing ultrasonic irradiation and CuBr as a catalyst. Subsequently, in the second step, we reacted the prepared enaminone with diethylmalonate, utilizing microwave irradiation. Moreover, a molecular docking study was performed to explore the binding mode of studied compound within the active site of Eg5 enzyme. The results showed a good stability of the 4-hydroxyquinoilone inside the cavity with an interesting docking score. Additionally, we conducted an in-silico investigation to predict the drug-likeness and ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the compound, utilizing MolSoft and SwissADME as precise predictive tools.

Fluoroquinolones (FQ) and sulfonamides (SA) are antibacterial substances used in therapeutics. Both are Active Pharmaceutical Ingredients (APIs) of low solubility. The solute-solvent interactions allow understanding drug´s absorption and the interactions involved in molecular recognition. This research aims to study Norfloxacin (NOR) and Sulfadiazine (SDZ) solvent interactions in pure solvents through experimental solvatochromism. Three apolar aprotic and six polar protic solvents were selected for this study. Multiparametric statistical analysis was performed with the method of linear solvation energy relationship of Kamlet and Taft, Catalan, and Laurence method. The results were analyzed by taking as reference the aprotic solvent, acetonitrile. In the case of SDZ, a shift towards shorter wavelengths (hypsochromic shifts) was observed when switching to nonpolar aprotic solvents, whereas in polar and some nonpolar protic solvents, the shifts were bathochromic (towards longer wavelengths). In the case of NOR, hypsochromic shifts were observed in most of the solvents tested, except 1-propanol, which exhibited a bathochromic shift. The Catalan and Laurence equation revealed that the highest relative contribution to NOR's behavior was attributed to the polarizability (π parameter), while for SDZ, it was the b parameter, representing hydrogen bond accepting capacity towards functional groups such as –NH₂, –SO₂NH, and –N, as indicated by the Kamlet and Taft and Catalan equations. The identification of key parameters contributing to these behaviors enhances our understanding of the solubility and molecular recognition of these antibacterial compounds.

Cancer represents one of the most serious diseases today, with a high mortality rate. Chemotherapy is a primary therapeutic method for the treatment of many cancers. In the middle of the last century, following the discovery that cis-diaminedichloroplatinum (III) (cisplatin) inhibited Escherichia coli cell division, platinum chemotherapeutics played a key role in the treatment of a wide range of malignancies. Although the use of these drugs in chemotherapy has shown success, it has been proven that platinum-based therapy shows many side effects, including severe neurotoxicity. Inhibition of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated upon DNA damage, represents one of the basic approaches to cancer treatment by applying targeted therapy. Platinum complexes are also widely used for this purpose. Finding new, less toxic drugs based on metal complexes would make a significant contribution to the treatment of malignancies. In this sense, the potential of the bifunctional Au(III) complexes to inhibit PARP was examined. For that purpose, [AuCl₂(bipy)]⁺ (bipy = 2.2'-bipyridine) complex, then complexes in which one and both Cl-atoms are substituted with L-cysteine are examined. The mentioned Au(III) complexes have been previously synthesized and experimentally investigated, but their theoretical study using molecular docking analysis was done here for the first time. The inhibitory activity of these gold complexes was compared with the inhibitory activity of cisplatin and oxyplatinum. Applied molecular docking analysis performed using AutoDock 4.0 program indicated that the highest inhibition potency possess monosubstituted Au(III)(bipy) complex (ΔG_bind= -8.74 kcal/mol, K_i= 0.40 μM), while somewhat lower inhibition potency has disubstituted Au(III)(bipy) complex (ΔG_bind= -7.19 kcal/mol, K_i= 5.40 μM) and initial [AuCl₂(bipy)]⁺ complex (ΔG_bind= -6.84 kcal/mol, K_i= 9.73 μM). The appropriate thermodynamical parameters that illustrates the inhibition potency of oxyplatinum are ΔG_bind= -7.12 kcal/mol, K_i= 6.01 μM, and of cisplatin those are ΔG_bind= -4.46 kcal/mol, K_i= 535.61 μM. Here performed theoretical study indicates that the investigated Au(III) complexes have the potential to be used for targeted therapy and that it would be important to investigate their biological activity in vitro and in vivo in detail.

Prostate cancer is known as hormone-sensitive, androgen dependent tumor and the second leading cause of cancer death in men. It is clear that androgens and androgen receptor signaling are crucial for prostate cancer growth and have been exploited therapeutically. However, hormone resistant prostate cancer is an unsolved problem with limited therapeutic choices. The action of androgens is mediated mainly through intracellular androgen receptors, which belong to the nuclear family of receptors. These receptors are transcription factors that determine key cell processes. A recent study by our team identified an alternative androgen receptor on the membrane of prostate cancer cells, OXER1 (5-oxo-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid receptor). Intrestingly, androgens via OXER1 inhibit cancer cell growth and migration. The aim of this research was to identify new molecules that will bind to the membrane receptor of androgens, OXER1 and will have antagonistic effects such as testosterone. To achieve this, we focused on natural products which there were data that may have a pharmacological effect and a therapeutic benefit in prostate cancer. Initially we performed in silico studies starting with the modeling of the interaction of OXER1 receptor with testosterone and 5-oxo-ETE. Due to the large number of natural products studied, an algorithm was designed and developed, allowing the fast and accurate classification of the examined chemical molecules. Next, using the advanced bioinformatics tool, OXER1 specific antagonists were identified. In vitro verification of the antagonistic properties of the selected compounds was performed in different cellular activities. The identified natural compounds, through bioinformatics methods, were tested in a number of cellular activities, related to the G_α and G_βγ activities of OXER1, such as cAMP, actin polymerization and their effect on calcium ion flow. In conclusion, the achievement of the present work is the identification of compounds as specific antagonists of OXER1. All these support that testosterone actions at the membrane level, via OXER1, can provide new targets and agents for possible novel therapeutic approaches in cancer.

ABSTRACT

Purpose

Metastatic cancer is a global concern. Invasion and metastasis are the hallmarks of cancer responsible for most cancer morbidity and mortality. Studies have suggested that an attack against these processes could cause a major breakthrough in cancer therapeutics. This research aimed at building the dataset of marine compounds reported to have effects on invasion and metastasis, and investigating their binding interactions, and stability with dual-specificity tyrosine regulated kinase 2 (DYRK2) through rigid receptor molecular docking, and molecular dynamics studies.

Method:

51 chemical compounds from 28 different species of marine organisms reported to have migrastatic activity in vitro/vivo were used. The dataset and SMILE strings for this study was generated using Chemsketch. The SwissADME (http://www.swissadme.ch/) and pkCSM (https://biosig.lab.uq.edu.au/pkcsm/prediction) webservers were used to predict the physiochemical and pharmacokinetic properties of the compounds after which ProTox-II (https://tox-new.charite.de/protox_II) was used to further evaluate their toxicity parameters. Compounds with drug-like properties were then subjected to in silico studies, investigating their binding interactions and stability with dual-specificity tyrosine regulated kinase 2 (DYRK2) through rigid receptor molecular docking, and molecular dynamics studies.

Result:

The compounds isolated from these organisms were mainly alkaloids and peptides, phenolics and polysaccharides with varying physicochemical, pharmacokinetic and toxicity properties. 4 compounds with high binding affinity, stability at the binding cavity of DYRK2, and low toxicity were selected, of which compound 5, normonanchoidine H, an alkaloid isolated from Monanchora pulchra, and compound 26, Bastadin A from Lanthella basta were the most promising lead molecules.

Conclusion:

We found that 51 chemical compounds from 28 different species of marine organisms were reported in literature to have migrastatic activity in vitro/vivo. Both molecular docking and molecular dynamics studies corroborated the in vitro/in vivo studies. Compounds 5 and 26, due to their high binding affinity to DYRK2, good pharmacokinetic profiles, low risks of toxicity and high stability in the binding site of the protein, have been found as potential lead molecules towards the development of efficacious and low risk toxic migrastatics.

Despite the complexity of research, high cost and time constraint, dengue research is undergoing a vast transformation with remarkable findings, include investigating the potential of plant-based compounds. A research investigated the potential of two flavonoids (clitorin and manghaslin) detected in Carica papaya leaf juice against dengue virus serotype-2 was conducted. This research used in silico model (docking simulation) in exploring the interaction of the two flavonoids on functional activity of two non-structural proteins involving in dengue viral ribonucleic acid (RNA) replication, i.e. NS2B/NS3 protease (NS2B/NS3) and NS5-RNA-dependent RNA polymerase (NS5-RdRp). The same flavonoids were then tested on in vitro model (plaque assay) to assess their antiviral effect through number of plaque forming units per mL. The docking simulation revealed the two flavonoids potentially bind onto the two targeted dengue proteins that are important for dengue viral replication but clitorin is predicted to have stronger binding interaction with the NS5-RdRp while manghaslin is predicted to have stronger binding interaction with the NS2B/NS3 protease. Both flavonoids inhibited the plaque formation. Other than in vivo research, the findings from this study also propose clitorin and manghaslin as a potential inhibitor of NS5-RdRp and NS2B/NS3 protease, which could be further investigated to exploit their drug likeness properties such as adsorption, distribution, metabolism and excretion.

In this research, a comprehensive analysis was conducted on 30 derivatives of naphthoquinone using computational methods such as 3D-QSAR modeling, assessment of drug similarity, ADMET analysis, molecular docking, and molecular dynamics simulations. The primary aim was to establish robust 3D-QSAR models employing CoMFA, aiming to identify potential novel antibacterial agents targeting Escherichia coli. The QSAR models exhibited strong predictive capabilities, as demonstrated by their assessments (Q² = 0.613, R² = 0.902, SEE = 0.063). Utilizing the QSAR model predictions, we devised four novel molecular structures. These structures were subsequently evaluated for drug likeness and ADMET predictions, with two compounds displaying exceptional ADMET predictions and drug likeness. Molecular docking was utilized to explore the interactions between the recently designed molecules, denoted as molecules 1 and 2, and the intended protein target. Of these, compound 2 displayed considerable stability based on the results obtained. To validate this stability, extensive molecular dynamics simulations were performed for 100 nanoseconds at three distinct temperatures, affirming the observed high stability.