Myricetin 3-rhamnoside retards the proliferation of hormone-independent breast cancer cells by targeting hyaluronidase.

Breast cancer is the second-leading cause of cancer-related death in women and the most often diagnosed malignancy. As the majority of chemotherapeutic medications are associated with recurrence, drug resistance, and side effects, scientists are shifting to beneficial agents for prevention and treatment, such as natural molecules. Myricetin 3-rhamnoside, a natural flavonol glycoside is known for diverse pharmacological activities but fewer reports describe the antiproliferative ability. The study aims to investigate the antiproliferative efficacy and target [hyaluronidase (HYAL) and ornithine decarboxylase (ODC), two poor breast cancer prognostic markers] modulatory potential of myricetin 3-rhamnoside on breast cancer cell lines using cytotoxicity assays and in silico docking, molecular dynamics analysis, cell-free and cell-based test methods. Myricetin 3-rhamnoside significantly retard the growth of MDA-MB-231 cells in SRB (IC50 88.64 ± 7.14 µM) and MTT (56.26 ± 8.50 µM) assay. It suppressed the transition of cells to the S-phase by inducing arrest in the G0/G1 phase with a fold change of 1.10. It shows robust binding interaction with ODC (-7.90 kcal/mol) and HYAL (-9.46 kcal/mol) and inhibits ODC (15.22 ± 2.61 µM) and HYAL (11.92 ± 2.89 µM) activity, but in a cell-based assay, the prominent response was observed against HYAL (21.46 ± 4.03 µM). Besides, it shows a 1.38 fold-down regulation of HYAL and forms a stable complex with HYAL. The binding pocket for myricetin 3-rhamnoside and the simulation pocket during the simulation are identical, indicating that myricetin 3-rhamnoside is actively blocking hyaluronidase. The computational prediction suggests it is a safe molecule. These observations imply that myricetin 3-rhamnoside could be used as a pharmacophore to design and synthesize a novel and safe agent for managing hormone-independent breast cancer.Communicated by Ramaswamy H. Sarma.

Myricitrin from bayberry as a potential inhibitor of cathepsin-D: Prospects for squamous lung carcinoma prevention.

Cathepsin-D (CATD) inhibitors' design and development drawn interest due to their potential therapeutic applications in managing different cancer types, including lung cancer. This study investigated myricitrin, a flavonol-3-O-rhamnoside, for its binding affinity to CATD. Molecular docking experiments revealed a strong binding affinity (-7.8 kcal/mol). Molecular dynamics (MD) simulation confirmed the complex's stability, while enzyme activity studies showed inhibitory concentration (IC50) of 35.14 ± 6.08 µM (in cell-free) and 16.00 ± 3.48 µM (in cell-based) test systems. Expression analysis indicated downregulation of CATD with a fold change of 1.35. Myricitrin demonstrated antiproliferative effects on NCIH-520 cells [IC50: 64.11 µM in Sulphorhodamine B (SRB), 24.44 µM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], but did not affect healthy CHANG cells. It also prolonged the G2/M phase (at 10 µM: 1.19-fold; at 100 µM: 1.13-fold) and increased sub-diploid population by 1.35-fold. Based on the analysis done using SwissADME program, it is predicted that myricitrin is not a cytochrome p450s (CYPs) inhibitor, followed the rule of Ghose and found not permeable to the blood-brain barrier (BBB) which suggests it as a safe molecule. In summary, the experimental findings may establish the foundation for myricitrin and its analogues to be used therapeutically in CATD-mediated lung cancer prevention.

Narirutin downregulates lipoxygenase-5 expression and induces G0/G1 arrest in triple-negative breast carcinoma cells.

BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer that does not express HER2, progesterone and estrogen receptors. It is associated with a high mortality rate, morbidity, metastasis, recurrence, poor prognosis and resistance to chemotherapy. Lipoxygenase-5 (LOX-5), cyclooxygenase-2 (COX-2), cathepsin-D (CATD), ornithine decarboxylase (ODC) and dihydrofolate reductase (DHFR) are involved in breast cancer carcinogenesis; hence, there is a pressing need to identify novel chemicals that targets these enzymes. Narirutin, a flavanone glycoside abundantly present in citrus fruits, is reported to have immune-modulatory, anti-allergic and antioxidant potential. Still, the cancer chemopreventive mechanism against TNBC has not been explored. METHODS: In vitro experiments, enzyme activity, expression analysis, molecular docking and MD simulation were carried out. RESULTS: Narirutin suppressed the growth of MDA-MB-231 and MCF-7 in a dose-proportional manner. The pronounced effect with >50% inhibition was observed in SRB and MTT assays for MDAMB-231 cells. Unexpectedly, narirutin suppressed the proliferation of normal cells (24.51%) at 100 µM. Further, narirutin inhibits the activity of LOX-5 in cell-free (18.18 ± 3.93 µM) and cell-based (48.13 ± 7.04 µM) test systems while moderately affecting COX-2, CATD, ODC and DHFR activity. Moreover, narirutin revealed a down-regulation of LOX-5 expression with a fold change of 1.23. Besides, MD simulation experiments confirm that narirutin binding forms a stable complex with LOX-5 and improves the stability and compactness of LOX-5. In addition, the prediction analysis demonstrates that narirutin could not cross the blood-brain barrier and did not act as an inhibitor of different CYPs. CONCLUSIONS AND SIGNIFICANCE: Narirutin could be a potent cancer chemopreventive lead for TNBC, further paving the way for synthesizing novel analogues.

Narirutin. A flavonoid found in citrus fruits modulates cell cycle phases and inhibits the proliferation of hormone-refractory prostate cancer cells by targeting hyaluronidase.

Narirutin is a dietary flavanone found in lemons, oranges, passion fruit, bergamot and grapefruit. It possesses anti-allergic, cardioprotective, neuroprotective, hepatoprotective potential, and its enriched fraction suppresses the growth of prostate cancer cells; however, there is currently no information on the chemopreventive potential of narirutin alone against hormone-refractory prostate cancer cells (PC-3) and its mode of action. Thus, the chemopreventive possibility of narirutin was investigated in PC-3 cells by utilising cytotoxicity assays. Further, a mechanism was deduced targeting hyaluronidase, an early-stage diagnosis marker, by cell-free, cell-based and in silico studies. The results indicate that narirutin reduced the viability of PC-3 cells with the inhibitory concentration range of 66.87-59.80 µM. It induced G0/G1 phase arrest with a fold change of 1.12. Besides, it increased the generation of reactive oxygen species (ROS) with a fold change of 1.34 at 100 µM. Narirutin inhibited hyaluronidase's activity in cell-free (11.17 µM) and cell-based assays (67.23 µM) and showed a strong binding interaction with hyaluronidase. Finally, the MD simulation analysis supported the idea that narirutin binding enhanced compactness and stability and created a stable complex with hyaluronidase. In addition, ADMET prediction indicates that it is a non-toxic, non-CYPs inhibitor and thus didn't alter the metabolism. The results reveal that narirutin may be a potential chemopreventive agent for hormone-resistant prostate cancer cells in addition to offering data for supporting diet-based nutraceutical agents to prevent prostate cancer.

Development of QSAR model using machine learning and molecular docking study of polyphenol derivatives against obesity as pancreatic lipase inhibitor.

In developed countries and developing countries, obesity/overweight is considered a major problem, in fact, it is now recognized as a major metabolic disorder. Additionally, obesity is connected with other metabolic diseases, including cardiovascular disorders, type 2 diabetes, some types of cancer, etc. Therefore, the development of novel drugs/medications for obesity is essential. The best target for treating obesity is Pancreatic Lipase (PL), it breaks 50-70% triglycerides into monoglycerol and free fatty acids.The major aim of this in silico study is to generate a QSAR model by using Multiple Linear Regression (MLR) and to inhibit pancreatic lipase by polyphenol derivatives mainly flavonoids, plant secondary metabolites shows good inhibitory activity against PL, maybe with less unpleasant side effects.In this in silico study, a potent inhibitor was found through calculating drug likness, QSAR (Quantitative structure-activity relationship) and molecular docking. The docking was performed in Maestro 12.0 and the ADME (absorption, distribution, metabolism, and excretion) properties (drug-likeness) of compounds/ligands were predicted by the Qikprop module of Maestro 12.0. The QSAR model was developed to show the relationship between the chemical/structural properties and the compound's biological activity. We have found the best interaction between pancreatic lipase and flavonoids. The best docked compound is Epigallocatechin 3,5,-di-O-gallate with docking score -10.935 kcal/mol .All compounds also show drug-likeness activity.The developed model has satisfied all internal and external validation criteria and has square correlation coefficient (r2) 0.8649, which shows its predictive ability and has good acceptability, predictive ability, and statistical robustness.Communicated by Ramaswamy H. Sarma.

Coumarin-based combined computational study to design novel drugs against Candida albicans.

Candida species cause the most prevalent fungal illness, candidiasis. Candida albicans is known to cause bloodstream infections. This species is a commensal bacterium, but it can cause hospital-acquired diseases, particularly in COVID-19 patients with impaired immune systems. Candida infections have increased in patients with acute respiratory distress syndrome. Coumarins are both naturally occurring and synthetically produced. In this study, the biological activity of 40 coumarin derivatives was used to create a three-dimensional quantitative structure activity relationship (3D-QSAR) model. The training and test minimum inhibitory concentration values of C. albicans active compounds were split, and a regression model based on statistical data was established. This model served as a foundation for the creation of coumarin derivative QSARs. This is a unique way to create new therapeutic compounds for various ailments. We constructed novel structural coumarin derivatives using the derived QSAR model, and the models were confirmed using molecular docking and molecular dynamics simulation.

Role of lupeol in chemosensitizing therapy-resistant prostate cancer cells by targeting MYC, ß-catenin and c-FLIP: in silico and in vitro studies.

Prostate cancer (CaP) is one of the most frequent malignancies amongst men. Enzalutamide is the second-generation potent androgen receptor (AR) antagonist used against metastatic and non-metastatic CaP. Unfortunately, the development of chemoresistance in cancer cells reduces the effectiveness of Enzalutamide. Lupeol is a pentacyclic triterpene found in different fruits, vegetables, and medicinal plants and possesses anti-inflammatory and anti-cancer properties. Here, we report in silico and in vitro studies of Lupeol and Enzalutamide against the ß-CATENIN, c-FLIPL, and c-MYC, which play a significant role in chemoresistance. We observed that Lupeol significantly inhibits the cell growth of chemoresistant Du145 cells and cancer stem cells (CSCs) either alone or in combination with Enzalutamide. Lupeol and Enzalutamide were also found to dock with ß-CATENIN, c-FLIPL, and c-MYC. The following MD simulation data showed both compounds exerting structural changes in these proteins. Finally, they significantly inhibit the transcriptional activity of all these genes, as observed by luciferase assay. Thus, we infer that Lupeol chemosensitizes the CaP cells for Enzalutamide-resistant CaP cells.

Subcutaneous Emphysema and Pneumomediastinum Following Non-invasive Ventilation in a Patient With Severe COVID-19 Disease.

Subcutaneous emphysema (SE) and pneumomediastinum are rare complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While SE is often non-fatal and usually self-remitting, pneumomediastinum can be fatal with high mortality rates depending on the underlying etiology. Here, we present the case of a 39-year-old otherwise healthy male who tested positive for SARS-CoV-2. The patient was treated with non-invasive mechanical ventilation (NIMV) and developed severe SE and pneumomediastinum which resulted in a fatal outcome. Although the exact pathogenesis could not be determined, the extensive lung injury caused by SARS-CoV-2 pneumonia along with possible barotrauma secondary to NIMV could have been the culprits in this case. Early detection through careful observation of these potentially fatal complications in patients with severe coronavirus disease 2019 is crucial. Further studies determining the potential risk factors and incidence of SE and pneumomediastinum, especially in patients receiving invasive mechanical ventilation or NIMV, are needed.

Identification of Severe Acute Respiratory Syndrome Coronavirus-2 inhibitors through in silico structure-based virtual screening and molecular interaction studies.

The novel coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) or COVID-19 has caused a worldwide pandemic. The fatal virus has affected the health of human beings as well as the socio-economic situation all over the world. To date, no concrete medicinal solution has been proposed to combat the viral infection, calling for an urgent, strategic, and cost-effective drug development approach that may be achievable by applying targeted computational and virtual screening protocols. Immunity is the body's natural defense against disease-causing pathogens, which can be boosted by consuming plant-based or natural food products. Active constituents derived from natural sources also scavenge the free radicals and have anti-inflammatory activities. Herbs and spices have been used for various medicinal purposes. In this study, 2,96 365 natural and synthetic derivatives (ligands) belonging to 102 classes of compounds were obtained from PubChem and assessed on Lipinski's parameters for their potential bioavailability. Out of all the derivatives, 3254 obeyed Lipinski's rule and were virtually screened. The 115 top derivatives were docked against SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-HKV1 main proteases (Mpro s) as receptors using AutoDock Vina, AutoDock, and iGEMDOCK 2.1. The lowest binding energy was exhibited by ligands 2 and 6 against all the four Mpro s. The molecular dynamic simulation was also performed with ligand 6 using the GROMACS package. Good bioactivity scores, absorption, distribution, metabolism, excretion, and toxicity profile and drug-like pharmacokinetic parameters were also obtained. Hydroxychloroquine was used as the control drug.

Effect of COVID-19 lockdown on noise pollution levels in an Indian city: a case study of Kanpur.

Noise pollution is an emerging environmental threat, prolonged exposure of which can cause annoyance, sleep disturbance, hypertension, psychiatric disorders, and also hormonal dysfunction. Among all the sources of noise pollution, the noise generated by road vehicle traffic significantly affects the quality of urban environments. Concerning the recent imposition of COVID-19 societal lockdown, this study attempts to investigate the impacts of COVID-19 lockdown on the changes in noise pollution levels before, during, and after lockdown phase in different residential, commercial, industrial, and silence zones of the city of Kanpur, India. Utilizing data collected from portable environmental sensors, the average noise levels before lockdown and during lockdown were found to be in the range of 44.85 dB to 79.57 dB and 38.55 dB to 57.79 dB, respectively, for different zones. Although a significant reduction in the noise levels was observed during lockdown, except for commercial zone, all other monitoring stations had reported sound levels quite higher than the recommended noise limits set by the Central Pollution Control Board (CPCB) of India. Results further indicated that the impact of road traffic noise on risk of high annoyance and sleep disturbance was found to be lower during lockdown as compared to that of pre-lockdown and unlock phase. While the annoyance level in residential (86.23%), industrial (87.44%), and silence (84.47%) was higher in pre-lockdown period, it reduced to 41.25, 50.28, and 43.07% in the lockdown phase. Even the risk of sleep disturbance in the residential zone was found to reduce from 37.96% during pre-lockdown to 14.72% during lockdown phase. Several noise mitigation strategies are also proposed, which may indeed pave the way for devising noise control measures in the local and regional level.

In silico validation of coumarin derivatives as potential inhibitors against Main Protease, NSP10/NSP16-Methyltransferase, Phosphatase and Endoribonuclease of SARS CoV-2.

Coronavirus Disease (COVID-19) is recently declared pandemic (WHO) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The virus was named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), (Coronavirus Disease 2019). Currently, there is no specific drug for the therapy of COVID-19. So, there is a need to develop or find out the new drug from the existing to cure the COVID-19. Identification of a potent inhibitor of Methyltransferase, Endoribonuclease, Phosphatase and Main Protease enzymes of SARS CoV-2 by coumarin derivatives using insilico approach. The in silico studies were performed on maestro 12.0 software (Schrodinger LLC 2019, USA). Two thousand seven hundred fifty-five biologically active coumarin derivative was docked with above receptor proteins of SARS CoV-2. The molecular dynamic simulation of the top one ligand of respected proteins was performed. Top five ligands of each protein were taken for study. Coumarin derivatives actively interact with taken receptors and showed good docking results for Methyltransferase, Endoribonuclease, Phosphatase and Main Protease and top five compounds of each have docking score from -9.00 to -7.97, -8.42 to -6.80, -8.63 to -7.48 and -7.30 to -6.01 kcal/mol, respectively. The docked compounds were showed RMSD and binding stability of simulated ligands are show the potency of ligands against the SARS CoV-2. Our study provides information on drugs that may be a potent inhibitor of COVID-19 infection. Drug repurposing of the available drugs would be great help in the treatment of COVID-19 infection. The combination therapy of the finding may improve inhibitory activity. Communicated by Ramaswamy H. SarmaHighlightsCoronavirus Disease (COVID-19) is recently declared pandemic (WHO) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).In silico virtual screening, docking, ADME, MM-GBSA and MD simulation analysis of coumarin derivatives against Methyltransferase (MTase), Endoribonuclease(endoU), ADP ribose Phosphatase and Main Protease enzyme of SARS CoV-2.All the analysis was performed on Maestro 12.0 Schrodinger software against respective receptors.Top five compounds of coumarin derivatives s docked at the active site of Methyltransferase (MTase), Endoribonuclease(endoU), ADP ribose Phosphatase and protease and top five compounds of each have docking score from -9.00 to -7.97, -8.42 to -6.80, -8.63 to -7.48 and -7.30 to -6.01 kcal/mol, respectively, of SARS CoV-2.These compounds were used to analysis of binding free energy by using the Prime MM-GBSA module.All the compounds showed drug-likeness properties.MD simulation of Proteins and ligands showed binding stability and good RMSD, radius of gyration of protein, coulomb-SR and LJ-SR energy.

Impact of COVID-19: A radical modal shift from public to private transport mode.

The unprecedented shock triggered by the COVID-19 pandemic has caused significant impact on public transportation services, travel behavior and mode choice preferences. Increasing risk of virus contagion in shared travel modes might result in a systemic shift from public transport to car commute. Such a shift causes increased congestions, emissions with a burden on the existing infrastructure. Given the urgent need of reconsideration of transport in a post-COVID world, this study presents insights into the possible shift from public transport to car commute due to the coronavirus crisis, potential factors influencing the mode shift, with emphasis being also laid on suitable strategies for promoting public transport use in the future world. Based on an online questionnaire survey conducted in India, results of logistic regression model indicate that commuters' socio-economic characteristics such as age, gender and monthly income tend to significantly influence mode switch preferences. In addition, trip characteristics including travel time, overcrowding and hygiene are strongly associated with mode shift preferences from public transport to car use. Commuters' perceptions on several strategies for promoting public transport have also been assessed, which will indeed pave the way for the formulation of post-COVID transport policies. In essence, efforts need to be directed towards restoring users' confidence and trust by providing a safe, secure and healthy environment to the public transport users.

Discovery of Novel Coumarin Analogs against the α-Glucosidase Protein Target of Diabetes Mellitus: Pharmacophore-Based QSAR, Docking, and Molecular Dynamics Simulation Studies.

Diabetes mellitus (DM) is a chronic metabolic disease, the third killer of mankind. The finding of potent drugs against diabetes remains challenging. In the present study, coumarin derivatives with known biological activity against diabetic protein have been used to predict functional groups' positions on coumarin derivatives. α-Glucosidase is a brush border membrane-bound lysosomal enzyme from the hydrolase enzyme family. It plays an important role in the metabolism of glycoproteins. Inhibitors of lysosomal α-glucosidase can reduce postprandial hyperglycemia. Due to this, lysosomal α-glucosidase is a good therapeutic target for drugs. A total of 116 coumarin derivatives with IC50 values against lysosomal α-glucosidase were selected for a CADD (computer-aided drug design) approach to identify more potent drugs. Pharmacophore modeling and atom-based 3-QSAR of 116 active compounds against lysosomal α-glucosidase were performed and identified positions and types of groups to increase activity. We performed molecular docking of 116 coumarin derivatives against the lysosomal α-glucosidase enzyme, and three compounds (isorutarine, 10_, and 36) resulted in a docking score of -7.64, -7.12, and -6.86 kcal/mol. The molecular dynamics simulation of the above three molecules and protein complex performed for 100 ns supported the interaction stability of isorutarine, 10_, and 36 with the lysosomal binding site α-glucosidase.

Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2.

Recently, a pathogen has been identified as a novel coronavirus (SARS-CoV-2) and found to trigger novel pneumonia (COVID-19) in human beings and some other mammals. The uncontrolled release of cytokines is seen from the primary stages of symptoms to last acute respiratory distress syndrome (ARDS). Thus, it is necessary to find out safe and effective drugs against this deadly coronavirus as soon as possible. Here, we downloaded the three-dimensional model of NSP10/NSP16 methyltransferase (PDB-ID: 6w6l) and main protease (PDB-ID: 6lu7) of COVID-19. Using these molecular models, we performed virtual screening with our anti-viral, inti-infectious, and anti-protease compounds, which are attractive therapeutics to prevent infection of the COVID-19. We found that top screened compound binds with protein molecules with good dock score with the help of hydrophobic interactions and hydrogen bonding. We observed that protease complexed with Cyclocytidine hydrochloride (anti-viral and anti-cancer), Trifluridine (anti-viral), Adonitol, and Meropenem (anti-bacterial), and Penciclovir (anti-viral) bound with a good docking score ranging from -6.8 to -5.1 (Kcal/mol). Further, NSP10/NSP16 methyltransferase complexed with Telbivudine, Oxytetracycline dihydrate (anti-viral), Methylgallate (anti-malarial), 2-deoxyglucose and Daphnetin (anti-cancer) from the docking score of -7.0 to -5.7 (Kcal/mol). In conclusion, the selected compounds may be used as a novel therapeutic agent to combat this deadly pandemic disease, SARS-CoV-2 infection, but needs further experimental research.HighlightsNSP10/NSP16 methyltransferase and main protease complex of SARS CoV-2 bind with selected drugs.NSP10/NSP16 methyltransferase and protease interacted with drugs by hydrophobic interactions.Compounds show good DG binging free energy with protein complexes.Ligands were found to follow the Lipinski rule of five.