Jusanin, a New Flavonoid from Artemisia commutata with an In Silico Inhibitory Potential against the SARS-CoV-2 Main Protease.

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and ß-sitosterol (4).

The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction.

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.

Chickpeas from a Chilean Region Affected by a Climate-Related Catastrophe: Effects of Water Stress on Grain Yield and Flavonoid Composition.

The Valparaiso region in Chile was decreed a zone affected by catastrophe in 2019 as a consequence of one of the driest seasons of the last 50 years. In this study, three varieties ('Alfa-INIA', 'California-INIA', and one landrace, 'Local Navidad') of kabuli-type chickpea seeds produced in 2018 (control) and 2019 (climate-related catastrophe, hereafter named water stress) were evaluated for their grain yield. Furthermore, the flavonoid profile of both free and esterified phenolic extracts was determined using liquid chromatography-mass spectrometry, and the concentration of the main flavonoid, biochanin A, was determined using liquid chromatography with diode array detection. The grain yield was decreased by up to 25 times in 2019. The concentration of biochanin A was up to 3.2 times higher in samples from the second season (water stress). This study demonstrates that water stress induces biosynthesis of biochanin A. However, positive changes in the biochanin A concentration are overshadowed by negative changes in the grain yield. Therefore, water stress, which may be worsened by climate change in the upcoming years, may jeopardize both the production of chickpeas and the supply of biochanin A, a bioactive compound that can be used to produce dietary supplements and/or nutraceuticals.

In silico molecular docking studies of certain commercially available flavonoids as effective antiviral agents against spike glycoprotein of SARS-CoV-2.

OBJECTIVE: Coronaviruses are large, enveloped, positive-stranded RNA viruses. These viruses contain spike-like projections of glycoprotein on their surface, which appear like a crown. Millions of infections and thousands of deaths have been reported worldwide to date. Hence, the objective of the present study was to look for in silico evaluation of certain commercially available flavonoids against SARS-CoV-2 enzyme. MATERIALS AND METHODS: The in silico docking calculations were carried out using AutoDock 4.2 software. For the computational investigation, Apigenin, Catechin, Galangin, Luteolin, Naringenin were selected. An anti-viral drug Remdesivir was selected as reference drug. RESULTS: In the present study we found that Naringenin showed excellent binding score with the SARS-CoV-2 enzyme compared to the reference drug and other selected flavonoids. CONCLUSIONS: Based on the docking results, we conclude that Naringenin can be considered worthwhile to check its antiviral activity for the management of Coronavirus disease.

Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease.

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 µM), and alphacoronavirus PEDV (IC50 value of 7.51 µM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.

A computational study of cooperative binding to multiple SARS-CoV-2 proteins.

Structure-based drug design targeting the SARS-CoV-2 virus has been greatly facilitated by available virus-related protein structures. However, there is an urgent need for effective, safe small-molecule drugs to control the spread of the virus and variants. While many efforts are devoted to searching for compounds that selectively target individual proteins, we investigated the potential interactions between eight proteins related to SARS-CoV-2 and more than 600 compounds from a traditional Chinese medicine which has proven effective at treating the viral infection. Our original ensemble docking and cooperative docking approaches, followed by a total of over 16-micorsecond molecular simulations, have identified at least 9 compounds that may generally bind to key SARS-CoV-2 proteins. Further, we found evidence that some of these compounds can simultaneously bind to the same target, potentially leading to cooperative inhibition to SARS-CoV-2 proteins like the Spike protein and the RNA-dependent RNA polymerase. These results not only present a useful computational methodology to systematically assess the anti-viral potential of small molecules, but also point out a new avenue to seek cooperative compounds toward cocktail therapeutics to target more SARS-CoV-2-related proteins.

The influence of microbiota-derived metabolites on viral infections.

Intestinal microbiota have profound effects on viral infections locally and systemically. While they can directly influence enteric virus infections, there is also an increasing appreciation for the role of microbiota-derived metabolites in regulating virus infections. Because metabolites diffuse across the intestinal epithelium and enter circulation, they can influence host response to pathogens at extraintestinal sites. In this review, we summarize the effects of three types of microbiota-derived metabolites on virus infections. While short-chain fatty acids serve to regulate the extent of inflammation associated with viral infections, the flavonoid desaminotyrosine and bile acids generally regulate interferon responses. A common theme that emerges is that microbiota-derived metabolites can have proviral and antiviral effects depending on the virus in question. Understanding the molecular mechanisms by which microbiota-derived metabolites impact viral infections and the highly conditional nature of these responses should pave the way to developing novel rational antivirals.

In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.

Computational guided identification of a citrus flavonoid as potential inhibitor of SARS-CoV-2 main protease.

Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (Mpro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of Mpro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to Mpro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with Mpro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of Mpro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.

Molecular Docking Studies of Bioactive Nicotiflorin against 6W63 Novel Coronavirus 2019 (COVID-19).

BACKGROUND: COVID-19 which is known as the novel coronavirus was reported in December 2019 in Wuhan city, China and many people have been contaminated by environmental contamination and transmission from one human to another until now. OBJECTIVE: The objective of the present work is to establish the inhibitory potential of nicotiflorin, a Kaempferol 3-O-rutinoside flavonoid, against the deadly coronavirus (COVID-19) 6W63 (main protease 3Clpro protein), using molecular docking approach. METHODS: The Molegro Virtual Docker software (MVD) with a 30 Å grid resolution was used. The structure was drawn by Chem 3D software and energy minimization was done by the MM2 force field. The protein 6W63 was downloaded from the protein data bank. Molegro modeller was used for score calculations. RESULT: The molecular docking studies were carried out on nicotiflorin and standard inhibitor X77, where standard inhibitor was observed in a co-crystallized state with main protease 3Clpro protein 6W63. The MolDock score, Rerank Sore, and H Bond score of nicotiflorin and standard inhibitor X77 were observed as -173.058, -127.302, -21.9398 and -156.913,-121.296,-5.7369, respectively. CONCLUSION: Molecular docking studies have confirmed that the affinity of flavonoid nicotiflorin with the amino acids of the viral protein 6W63 was relatively more than the standard X77. For the effective treatment of novel coronavirus COVID-19, the effectiveness of the identified flavonoid nicotiflorin can further be evaluated for safety and efficacy parameters at both preclinical and clinical stages.