In Silico Identification and Analysis of Potentially Bioactive Antiviral Phytochemicals against SARS-CoV-2: A Molecular Docking and Dynamics Simulation Approach.

SARS-CoV-2, a deadly coronavirus sparked COVID-19 pandemic around the globe. With an increased mutation rate, this infectious agent is highly transmissible inducing an escalated rate of infections and death everywhere. Hence, the discovery of a viable antiviral therapy option is urgent. Computational approaches have offered a revolutionary framework to identify novel antimicrobial treatment regimens and allow a quicker, cost-effective, and productive conversion into the health center by evaluating preliminary and safety investigations. The primary purpose of this research was to find plausible plant-derived antiviral small molecules to halt the viral entrance into individuals by clogging the adherence of Spike protein with human ACE2 receptor and to suppress their genome replication by obstructing the activity of Nsp3 (Nonstructural protein 3) and 3CLpro (main protease). An in-house library of 1163 phytochemicals were selected from the NPASS and PubChem databases for downstream analysis. Preliminary analysis with SwissADME and pkCSM revealed 149 finest small molecules from the large dataset. Virtual screening using the molecular docking scoring and the MM-GBSA data analysis revealed that three candidate ligands CHEMBL503 (Lovastatin), CHEMBL490355 (Sulfuretin), and CHEMBL4216332 (Grayanoside A) successfully formed docked complex within the active site of human ACE2 receptor, Nsp3, and 3CLpro, respectively. Dual method molecular dynamics (MD) simulation and post-MD MM-GBSA further confirmed efficient binding and stable interaction between the ligands and target proteins. Furthermore, biological activity spectra and molecular target analysis revealed that all three preselected phytochemicals were biologically active and safe for human use. Throughout the adopted methodology, all three therapeutic candidates significantly outperformed the control drugs (Molnupiravir and Paxlovid). Finally, our research implies that these SARS-CoV-2 protein antagonists might be viable therapeutic options. At the same time, enough wet lab evaluations would be needed to ensure the therapeutic potency of the recommended drug candidates for SARS-CoV-2.

Selected Phytochemicals to Combat Lungs Injury: Natural Care.

The human has two lungs responsible for respiration and drug metabolism. Severe lung infection caused by bacteria, mycobacteria, viruses, fungi, and parasites may lead to lungs injury. Smoking and tobacco consumption may also produce lungs injury. Inflammatory and pain mediators are secreted by alveolar macrophages. The inflammatory mediators, such as cytokines, interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, neutrophils, and fibroblasts are accumulated in the alveoli sac, which becomes infected. It may lead to hypoxia followed by severe pulmonary congestion and the death of the patient. There is an urgent need for the treatment of artificial respiration and ventilation. However, the situation may be the worst for patients suffering from lung cancer, pulmonary tuberculosis, and acute pneumonia caused by acute respiratory distress syndrome (ARDS). Re-urgency has been happening in the case of coronavirus disease of 2019 (COVID-19) patients. Therefore, it is needed to protect the lungs with the intake of natural phytomedicines. In the present review, several selected phyto components having the potential role in lung injury therapy have been discussed. Regular intake of natural vegetables and fruits bearing these constituents may save the lungs even in the dangerous attack of SARS-CoV-2 in lung cancer, pulmonary TB, and pneumatic patients.

Ethnopharmacological Potential of Phytochemicals and Phytogenic Products against Human RNA Viral Diseases as Preventive Therapeutics.

RNA viruses have been the most destructive due to their transmissibility and lack of control measures. Developments of vaccines for RNA viruses are very tough or almost impossible as viruses are highly mutable. For the last few decades, most of the epidemic and pandemic viral diseases have wreaked huge devastation with innumerable fatalities. To combat this threat to mankind, plant-derived novel antiviral products may contribute as reliable alternatives. They are assumed to be nontoxic, less hazardous, and safe compounds that have been in uses in the beginning of human civilization. In this growing COVID-19 pandemic, the present review amalgamates and depicts the role of various plant products in curing viral diseases in humans.

Curative Potential of High-Value Phytochemicals on COVID-19 Infection.

Medicinal plants and their therapeutically promising chemical compounds belonging to the valued category of 'traditional medicine' are potential remedies for various health problems. Due to their complex structure and enormous health benefits, the high-value plant-derived metabolites collectively termed as 'phytochemicals' have emerged as a crucial source for novel drug discovery and development. Indeed, several medicinal plants from diverse habitats are still in the 'underexplored' category in terms of their bioactive principles and therapeutic potential. COVID-19, infection caused by the SARS-CoV-2, first reported in November 2019, resulted in the alarming number of deaths (6.61 million), was further declared 'pandemic', and spread of the disease has continued till today. Even though the well-established scientific world has successfully implemented vaccines against COVID-19 within the short period of time, the focus on alternative remedies for long-term symptom management and immunity boosting have been increased. At this point, interventions based on traditional medicine, which include medicinal plants, their bioactive metabolites, extracts and formulations, attracted a lot of attention as alternative solutions for COVID-19 management. Here, we reviewed the recent research findings related to the effectiveness of phytochemicals in treatment or prevention of COVID-19. Furthermore, the literature regarding the mechanisms behind the preventive or therapeutic effects of these natural phytochemicals were also discussed. In conclusion, we suggest that the active plant-derived components could be used alone or in combination as an alternative solution for the management of SARS-CoV-2 infection. Moreover, the structure of these natural productomes may lead to the emergence of new prophylactic strategies for SARS-CoV-2-caused infection.

Barbaloin: an amazing chemical from the 'wonder plant' with multidimensional pharmacological attributes.

Aloe vera (L.) Burm.f. is nicknamed the 'Miracle plant' or sometimes as the 'Wonder plant'. It is a plant that has been used since ancient times for the innumerable health benefits associated with it. It is one of the important plants that has its use in conventional medicinal treatments. It is a perennial succulent, drought-tolerant member of the family Asphodelaceae. There are scores of properties associated with the plant that help in curing various forms of human ailments. Extracts and gels obtained from plants have been shown to be wonderful healers of different conditions, mainly various skin problems. Also, this plant is popular in the cosmetics industry. The underlying properties of the plant are now mainly associated with the natural phytochemicals present in the plant. Diverse groups of phytoingredients are found in the plant, including various phenolics, amino acids, sugars, vitamins, and different other organic compounds, too. One of the primary ingredients found in the plant is the aloin molecule. It is an anthraquinone derivative and exists as an isomer of Aloin A and Aloin B. Barbaloin belonging to the first group is a glucoside of the aloe-emodin anthrone molecule. Various types of pharmacological properties exhibited by the plant can be attributed to this chemical. Few significant ones are antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, anti-microbial, and anti-viral, along with their different immunity-boosting actions. Recently, molecular coupling studies have also found the role of these molecules as a potential cure against the ongoing COVID-19 disease. This study comprehensively focuses on the numerous pharmacological actions of the primary compound barbaloin obtained from the Aloe vera plant along with the mechanism of action and the potent application of these natural molecules under various conditions.

Biochanin A as a modulator of the inflammatory response: An updated overview and therapeutic potential.

Uncontrolled inflammation and failure to resolve the inflammatory response are crucial factors involved in the progress of inflammatory diseases. Current therapeutic strategies aimed at controlling excessive inflammation are effective in some cases, though they may be accompanied by severe side effects, such as immunosuppression. Phytochemicals as a therapeutic alternative can have a fundamental impact on the different stages of inflammation and its resolution. Biochanin A (BCA) is an isoflavone known for its wide range of pharmacological properties, especially its marked anti-inflammatory effects. Recent studies have provided evidence of BCA's abilities to activate events essential for resolving inflammation. In this review, we summarize the most recent findings from pre-clinical studies of the pharmacological effects of BCA on the complex signaling network associated with the onset and resolution of inflammation and BCA's potential protective functionality in several models of inflammatory diseases, such as arthritis, pulmonary disease, neuroinflammation, and metabolic disease.

Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CLPro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity.

The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge in patients and the lack of drug efficacy for treatment. SARS-CoV-2 3CLPro is one of the most intriguing biomolecular targets among scientists worldwide for developing antiviral drugs due to its relevance in viral replication and transcription. Herein, we utilized computer-assisted drug screening to investigate 326 natural products from Thai traditional plants using structure-based virtual screening against SARS-CoV-2 3CLPro. Following the virtual screening, the top 15 compounds based on binding energy and their interactions with key amino acid Cys145 were obtained. Subsequently, they were further evaluated for protein-ligand complex stability via molecular dynamics simulation and binding free energy calculation using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches. Following drug-likeness and ADME/Tox assessments, seven bisbenzylisoquinolines were obtained, including neferine (3), liensinine (4), isoliensinine (5), dinklacorine (8), tiliacorinine (13), 2'-nortiliacorinine (14), and yanangcorinine (15). These compounds computationally showed a higher binding affinity than native N3 and GC-373 inhibitors and attained stable interactions on the active site of 3CLpro during 100 ns in molecular dynamics (MD) simulation. Moreover, the in vitro enzymatic assay showed that most bisbenzylisoquinolines could experimentally inhibit SARS-CoV-2 3CLPro. To our delight, isoliensinine (5) isolated from Nelumbo nucifera demonstrated the highest inhibition of protease activity with the IC50 value of 29.93 µM with low toxicity on Vero cells. Our findings suggested that bisbenzylisoquinoline scaffolds could be potentially used as an in vivo model for the development of effective anti-SARS-CoV-2 drugs.

In Silico Identification of 1-DTP Inhibitors of Corynebacterium diphtheriae Using Phytochemicals from Andrographis paniculata.

A number of phytochemicals have been identified as promising drug molecules against a variety of diseases using an in-silico approach. The current research uses this approach to identify the phyto-derived drugs from Andrographis paniculata (Burm. f.) Wall. ex Nees (AP) for the treatment of diphtheria. In the present study, 18 bioactive molecules from Andrographis paniculata (obtained from the PubChem database) were docked against the diphtheria toxin using the AutoDock vina tool. Visualization of the top four molecules with the best dockscore, namely bisandrographolide (-10.4), andrographiside (-9.5), isoandrographolide (-9.4), and neoandrographolide (-9.1), helps gain a better understanding of the molecular interactions. Further screening using molecular dynamics simulation studies led to the identification of bisandrographolide and andrographiside as hit compounds. Investigation of pharmacokinetic properties, mainly ADMET, along with Lipinski's rule and binding affinity considerations, narrowed down the search for a potent drug to bisandrographolide, which was the only molecule to be negative for AMES toxicity. Thus, further modification of this compound followed by in vitro and in vivo studies can be used to examine itseffectiveness against diphtheria.

An Attention towards the Prophylactic and Therapeutic Options of Phytochemicals for SARS-CoV-2: A Molecular Insight.

The novel pathogenic virus was discovered in Wuhan, China (December 2019), and quickly spread throughout the world. Further analysis revealed that the pathogenic strain of virus was corona but it was distinct from other coronavirus strains, and thus it was renamed 2019-nCoV or SARS-CoV-2. This coronavirus shares many characteristics with other coronaviruses, including SARS-CoV and MERS-CoV. The clinical manifestations raised in the form of a cytokine storm trigger a complicated spectrum of pathophysiological changes that include cardiovascular, kidney, and liver problems. The lack of an effective treatment strategy has imposed a health and socio-economic burden. Even though the mortality rate of patients with this disease is lower, since it is judged to be the most contagious, it is considered more lethal. Globally, the researchers are continuously engaged to develop and identify possible preventive and therapeutic regimens for the management of disease. Notably, to combat SARS-CoV-2, various vaccine types have been developed and are currently being tested in clinical trials; these have also been used as a health emergency during a pandemic. Despite this, many old antiviral and other drugs (such as chloroquine/hydroxychloroquine, corticosteroids, and so on) are still used in various countries as emergency medicine. Plant-based products have been reported to be safe as alternative options for several infectious and non-infectious diseases, as many of them showed chemopreventive and chemotherapeutic effects in the case of tuberculosis, cancer, malaria, diabetes, cardiac problems, and others. Therefore, plant-derived products may play crucial roles in improving health for a variety of ailments by providing a variety of effective cures. Due to current therapeutic repurposing efforts against this newly discovered virus, we attempted to outline many plant-based compounds in this review to aid in the fight against SARS-CoV-2.

Virtual screening of phytochemicals by targeting multiple proteins of severe acute respiratory syndrome coronavirus 2: Molecular docking and molecular dynamics simulation studies.

OBJECTIVE: Medicinal herbs are being investigated for medicationhg development against SARS-CoV-2 as a rich source of bioactive chemicals. One of the finest approaches for finding therapeutically effective drug molecules in real time is virtual screening scheme such as molecular docking in conjunction with molecular dynamics (MD) simulation. These virtual techniques provide an ample opportunity for the screening of plausible inhibitors of SARS-CoV-2 different target proteins from a comprehensive and extensive phytochemical library. The study was designed to identify potential phytochemicals by virtual screening against different receptor proteins. METHODS: In the current study, a library of plant secondary metabolites was created by manually curating 120 phytochemicals known to have antimicrobial as well as antiviral properties. In the current study, different potential phytochemicals were identified by virtual screening against various selected receptor proteins (i.e., viral main proteases, RNA-dependent RNA polymerase (RdRp), ADP ribose phosphatase, nonstructural proteins NSP7, NSP8, and NSP9) which are key proteins responsible for transcription, replication and maturation of SARS-CoV-2 in the host. Top three phytochemicals were selected against each viral receptor protein based on their best S-scores, RMSD values, molecular interactions, binding patterns and drug-likeness properties. RESULTS: The results of molecular docking study revealed that phytochemicals (i.e., baicalin, betaxanthin, epigallocatechin, fomecin A, gallic acid, hortensin, ichangin, kaempferol, limonoic acid, myricetin hexaacetat, pedalitin, quercetin, quercitrin, and silvestrol) have strong antiviral potential against SARS-CoV-2. Additionally, the reported preeminent reliable phytochemicals also revealed toxicity by no means during the evaluation through ADMET profiling. Moreover, the MD simulation study also exhibited thermal stability and stable binding affinity of the pedalitin with SARS-CoV-2 RdRp and SARS-CoV-2 main protease which suggests appreciable efficacy of the lead optimization. CONCLUSION: The biological activity and pharmacologically distinguishing characteristics of these lead compounds also satisfied as repurposing antiviral drug contenders and are worth substantial evaluation in the biological laboratory for the recommendation of being plausible antiviral drug candidates against SARS-CoV-2.

Virtual Screening of Artemisia annua Phytochemicals as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronaviruses that emerged in China at Wuhan city, Hubei province during December 2019. Subsequently, SARS-CoV-2 has spread worldwide and caused millions of deaths around the globe. Several compounds and vaccines have been proposed to tackle this crisis. Novel recommended in silico approaches have been commonly used to screen for specific SARS-CoV-2 inhibitors of different types. Herein, the phytochemicals of Pakistani medicinal plants (especially Artemisia annua) were virtually screened to identify potential inhibitors of the SARS-CoV-2 main protease enzyme. The X-ray crystal structure of the main protease of SARS-CoV-2 with an N3 inhibitor was obtained from the protein data bank while A. annua phytochemicals were retrieved from different drug databases. The docking technique was carried out to assess the binding efficacy of the retrieved phytochemicals; the docking results revealed that several phytochemicals have potential to inhibit the SARS-CoV-2 main protease enzyme. Among the total docked compounds, the top-10 docked complexes were considered for further study and evaluated for their physiochemical and pharmacokinetic properties. The top-3 docked complexes with the best binding energies were as follows: the top-1 docked complex with a -7 kcal/mol binding energy score, the top-2 docked complex with a -6.9 kcal/mol binding energy score, and the top-3 docked complex with a -6.8 kcal/mol binding energy score. These complexes were subjected to a molecular dynamic simulation analysis for further validation to check the dynamic behavior of the selected top-complexes. During the whole simulation time, no major changes were observed in the docked complexes, which indicated complex stability. Additionally, the free binding energies for the selected docked complexes were also estimated via the MM-GB/PBSA approach, and the results revealed that the total delta energies of MMGBSA were -24.23 kcal/mol, -26.38 kcal/mol, and -25 kcal/mol for top-1, top-2, and top-3, respectively. MMPBSA calculated the delta total energy as -17.23 kcal/mol (top-1 complex), -24.75 kcal/mol (top-2 complex), and -24.86 kcal/mol (top-3 complex). This study explored in silico screened phytochemicals against the main protease of the SARS-CoV-2 virus; however, the findings require an experimentally based study to further validate the obtained results.

Regulation of Cholesterol Metabolism by Phytochemicals Derived from Algae and Edible Mushrooms in Non-Alcoholic Fatty Liver Disease.

Cholesterol synthesis occurs in almost all cells, but mainly in hepatocytes in the liver. Cholesterol is garnering increasing attention for its central role in various metabolic diseases. In addition, cholesterol is one of the most essential elements for cells as both a structural source and a player participating in various metabolic pathways. Accurate regulation of cholesterol is necessary for the proper metabolism of fats in the body. Disturbances in cholesterol homeostasis have been linked to various metabolic diseases, such as hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). For many years, the use of synthetic chemical drugs has been effective against many health conditions. Furthermore, from ancient to modern times, various plant-based drugs have been considered local medicines, playing important roles in human health. Phytochemicals are bioactive natural compounds that are derived from medicinal plants, fruit, vegetables, roots, leaves, and flowers and are used to treat a variety of diseases. They include flavonoids, carotenoids, polyphenols, polysaccharides, vitamins, and more. Many of these compounds have been proven to have antioxidant, anti-inflammatory, antiobesity and antihypercholesteremic activity. The multifaceted role of phytochemicals may provide health benefits to humans with regard to the treatment and control of cholesterol metabolism and the diseases associated with this disorder, such as NAFLD. In recent years, global environmental climate change, the COVID-19 pandemic, the current war in Europe, and other conflicts have threatened food security and human nutrition worldwide. This further emphasizes the urgent need for sustainable sources of functional phytochemicals to be included in the food industry and dietary habits. This review summarizes the latest findings on selected phytochemicals from sustainable sources-algae and edible mushrooms-that affect the synthesis and metabolism of cholesterol and improve or prevent NAFLD.

Identification of phytochemicals in Qingfei Paidu decoction for the treatment of coronavirus disease 2019 by targeting the virus-host interactome.

Qingfei Paidu decoction (QFPDD) has been clinically proven to be effective in the treatment of coronavirus disease 2019 (COVID-19). However, the bioactive components and therapeutic mechanisms remain unclear. This study aimed to explore the effective components and underlying mechanisms of QFPDD in the treatment of COVID-19 by targeting the virus-host interactome and verifying the antiviral activities of its active components in vitro. Key active components and targets were identified by analysing the topological features of a compound-target-pathway-disease regulatory network of QFPDD for the treatment of COVID-19. The antiviral activity of the active components was determined by a live virus infection assay, and possible mechanisms were analysed by pseudotyped virus infection and molecular docking assays. The inhibitory effects of the components tested on the virus-induced release of IL-6, IL-1ß and CXCL-10 were detected by ELISA. Three components of QFPDD, oroxylin A, hesperetin and scutellarin, exhibited potent antiviral activities against live SARS-CoV-2 virus and HCoV-OC43 virus with IC50 values ranging from 18.68 to 63.27 µM. Oroxylin A inhibited the entry of SARS-CoV-2 pseudovirus into target cells and inhibited SARS-CoV-2 S protein-mediated cell-cell fusion by binding with the ACE2 receptor. The active components of QFPDD obviously inhibited the IL-6, IL-1ß and CXCL-10 release induced by the SARS-CoV-2 S protein. This study supports the clinical application of QFPDD and provides an effective analysis method for the in-depth study of the mechanisms of traditional Chinese medicine (TCM) in the prevention and treatment of COVID-19.

Molecular Mechanisms of Anti-Inflammatory Phytochemicals.

Naturally occurring bioactives, also known as phytochemicals, have been widely recognized and researched owing to their multiple potentialities [...].

Antiviral COVID-19 protein and molecular docking: In silico characterization of various antiviral compounds extracted from Arisaema jacquemontii Blume.

Arisaema jacquemontii Blume is a highly medicinal and poisonous plant belong to the family Araceae. It is used to treat several deadly diseases, including viral infections. It has antioxidant, anti-cancerous, antimalarial, anti-vermicidal, and antiviral activities. Therefore, five parts of the Arisaema jacquemontii Blume plant, such as leaf, seed, stem, pulp, and rhizome extract, were evaluated for metabolic and in silico characterization of probable compounds using gas chromatography-mass spectrometry (GC-MS) analysis. A total of 22 compounds were isolated from the methanolic extracts of A. jacquemontii Blume. A selected antiviral COVID-19 protein i.e., protease (6LU7) was docked against the obtained compounds. Different affinities were obtained through various compounds. The best results were shown by three different compounds identified in the rhizome. The maximum binding affinity of these compounds is 8.1 kJ/mol. Molecular docking (MD) indicate that these molecules have the highest binding energies and hydrogen bonding interactions. The binding mode of interaction was discovered to be reasonably effective for counteracting the SARS virus COVID-19. The findings of this study could be extremely useful in the development of more phytochemical-based COVID-19 therapeutics.

Brassica Genus Seeds: A Review on Phytochemical Screening and Pharmacological Properties.

Traditionally, Brassica species are widely used in traditional medicine, human food, and animal feed. Recently, special attention has been dedicated to Brassica seeds as source of health-promoting phytochemicals. This review provides a summary of recent research on the Brassica seed phytochemistry, bioactivity, dietary importance, and toxicity by screening the major online scientific database sources and papers published in recent decades by Elsevier, Springer, and John Wiley. The search was conducted covering the period from January 1964 to July 2022. Phytochemically, polyphenols, glucosinolates, and their degradation products were the predominant secondary metabolites in seeds. Different extracts and their purified constituents from seeds of Brassica species have been found to possess a wide range of biological properties including antioxidant, anticancer, antimicrobial, anti-inflammatory, antidiabetic, and neuroprotective activities. These valuable functional properties of Brassica seeds are related to their richness in active compounds responsible for the prevention and treatment of various chronic diseases such as obesity, diabetes, cancer, and COVID-19. Currently, the potential properties of Brassica seeds and their components are the main focus of research, but their toxicity and health risks must also be accounted for.

The Efficacy of Traditional Medicinal Plants in Modulating the Main Protease of SARS-CoV-2 and Cytokine Storm.

Selected traditional medicinal plants exhibit therapeutic effects in coronavirus disease (Covid-19) patients. This review aims to identify the phytochemicals from five traditional medicinal plants (Glycyrrhiza glabra, Nigella sativa, Curcuma longa, Tinospora cordifolia and Withania somnifera) with high potential in modulating the main protease (Mpro) activity and cytokine storm in Covid-19 infection. The Mpro binding affinity of 13 plant phytochemicals were in the following order: Withanoside II>withanoside IV>withaferin A>α-hederin>withanoside V>sitoindoside IX>glabridin>liquiritigenin, nigellidine>curcumin>glycyrrhizin>tinocordiside>berberine. Among these phytochemicals, glycyrrhizin, withaferin A, curcumin, nigellidine and cordifolioside A suppressed SARS-CoV-2 replication and showed stronger anti-inflammatory activities than standard Covid-19 drugs. Both preclinical and clinical evidences supported the development of plant bioactive compounds as Mpro inhibitors.

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections generate approximately one million virions per day, and the majority of available antivirals are ineffective against it due to the virus's inherent genetic mutability. This necessitates the investigation of concurrent inhibition of multiple SARS-CoV-2 targets. We show that fortunellin (acacetin 7-O-neohesperidoside), a phytochemical, is a promising candidate for preventing and treating coronavirus disease (COVID-19) by targeting multiple key viral target proteins. Fortunellin supports protective immunity while inhibiting pro-inflammatory cytokines and apoptosis pathways and protecting against tissue damage. Fortunellin is a phytochemical found in Gojihwadi kwath, an Indian traditional Ayurvedic formulation with an antiviral activity that is effective in COVID-19 patients. The mechanistic action of its antiviral activity, however, is unknown. The current study comprehensively evaluates the potential therapeutic mechanisms of fortunellin in preventing and treating COVID-19. We have used molecular docking, molecular dynamics simulations, free-energy calculations, host target mining of fortunellin, gene ontology enrichment, pathway analyses, and protein-protein interaction analysis. We discovered that fortunellin reliably binds to key targets that are necessary for viral replication, growth, invasion, and infectivity including Nucleocapsid (N-CTD) (-54.62 kcal/mol), Replicase-monomer at NSP-8 binding site (-34.48 kcal/mol), Replicase-dimer interface (-31.29 kcal/mol), Helicase (-30.02 kcal/mol), Papain-like-protease (-28.12 kcal/mol), 2'-O-methyltransferase (-23.17 kcal/mol), Main-protease (-21.63 kcal/mol), Replicase-monomer at dimer interface (-22.04 kcal/mol), RNA-dependent-RNA-polymerase (-19.98 kcal/mol), Nucleocapsid-NTD (-16.92 kcal/mol), and Endoribonuclease (-16.81 kcal/mol). Furthermore, we identify and evaluate the potential human targets of fortunellin and its effect on the SARS-CoV-2 infected tissues, including normal-human-bronchial-epithelium (NHBE) and lung cells and organoids such as pancreatic, colon, liver, and cornea using a network pharmacology approach. Thus, our findings indicate that fortunellin has a dual role; multi-target antiviral activities against SARS-CoV-2 and immunomodulatory capabilities against the host.

A review on computational approaches that support the researches on traditional Chinese medicines (TCM) against COVID-19.

BACKGROUND: COVID-19 highly caused contagious infections and massive deaths worldwide as well as unprecedentedly disrupting global economies and societies, and the urgent development of new antiviral medications are required. Medicinal herbs are promising resources for the discovery of prophylactic candidate against COVID-19. Considerable amounts of experimental efforts have been made on vaccines and direct-acting antiviral agents (DAAs), but neither of them was fast and fully developed. PURPOSE: This study examined the computational approaches that have played a significant role in drug discovery and development against COVID-19, and these computational methods and tools will be helpful for the discovery of lead compounds from phytochemicals and understanding the molecular mechanism of action of TCM in the prevention and control of the other diseases. METHODS: A search conducting in scientific databases (PubMed, Science Direct, ResearchGate, Google Scholar, and Web of Science) found a total of 2172 articles, which were retrieved via web interface of the following websites. After applying some inclusion and exclusion criteria and full-text screening, only 292 articles were collected as eligible articles. RESULTS: In this review, we highlight three main categories of computational approaches including structure-based, knowledge-mining (artificial intelligence) and network-based approaches. The most commonly used database, molecular docking tool, and MD simulation software include TCMSP, AutoDock Vina, and GROMACS, respectively. Network-based approaches were mainly provided to help readers understanding the complex mechanisms of multiple TCM ingredients, targets, diseases, and networks. CONCLUSION: Computational approaches have been broadly applied to the research of phytochemicals and TCM against COVID-19, and played a significant role in drug discovery and development in terms of the financial and time saving.

Geographic Variability of Berry Phytochemicals with Antioxidant and Antimicrobial Properties.

The aim of this study was to determine the variability of several chemical compounds and the antioxidant and antimicrobial activities of eight types of berries harvested from two different geographical regions in the same year. The analyses were performed on bilberry, black currant, gooseberry, red currant, raspberry, sea buckthorn, strawberry and sour cherry, which were handpicked during the summer of 2019, in the same periods when they are typically harvested for consumer purposes. Total anthocyanins content (TAC), total flavonoids content (TFC), total polyphenolic compounds (TPC), determination of the Ferric-Reducing Antioxidant Power (FRAP), determination of the DPPH free radical scavenging assay (RSA), determination of nine phenolic compounds by HPLC-UV assay and antimicrobial activity were determined for undiluted hydroalcoholic extracts of all the studied berries. The results showed that the berries from Romania were richer in antioxidant compounds than the berries from Russia. The TPC content varied between 4.13-22.2 mg GAE/g d.w., TFC between 3.33-8.87 mg QE/g d.w. and TAC between 0.13-3.94 mg/g d.w. The highest variability was determined for TPC. Regarding the antioxidant activity assessed by FRAP assay, values were between 6.02-57.23 µmols TE/g d.w. and values for the RSA method between 18.44-83.81%. From the eight types of berries analyzed, bilberries and raspberries had the highest antioxidant activity considering both regions and both determination methods. Not only the type, but also the environmental and cultivation conditions in which the berries grow, can lead to variations in their chemical composition. The extracted polyphenolic compounds from the studied berries showed antibacterial properties on pathogens, such as Escherichia coli, Bacillus subtilis and Staphyloccocus aureus. The inhibitory action on Salmonella typhi and fungi Candida albicans and Aspegillus niger was absent to very low. The antimicrobial activity of the hydroalcoholic extracts was dependent on the provenance of the berries, too.