Multifaceted antiviral therapeutic potential of dietary flavonoids: Emerging trends and future perspectives.

Phytochemicals are the natural biomolecules produced by plants via primary or secondary metabolism, which have been known to have many potential health benefits to human beings. Flavonoids or phytoestrogens constitute a major group of such phytochemicals widely available in variety of vegetables, fruits, herbs, tea, and so forth, implicated in a variety of bio-pharmacological and biochemical activities against diseases including bacterial, viral, cancer, inflammatory, and autoimmune disorders. More recently, these natural biomolecules have been shown to have effective antiviral properties via therapeutically active ingredients within them, acting at different stages of infection. Current review emphasizes upon the role of these flavonoids in physiological functions, prevention and treatment of viral diseases. More so the review focuses specifically upon the antiviral effects exhibited by these natural biomolecules against RNA viruses including coronaviruses. Furthermore, the article would certainly provide a lead to the scientific community for the effective therapeutic antiviral use of flavonoids using potential cost-effective tools for improvement of the pharmacokinetics, bioavailability, and biodistribution of such compounds for the concrete action along with the promotion of human health.

Antiviral Efficacy of Selected Natural Phytochemicals against SARS-CoV-2 Spike Glycoprotein Using Structure-Based Drug Designing.

SARS-CoV-2 is a highly virulent coronavirus that first surfaced in late 2019 and has since created a pandemic of the acute respiratory sickness known as "coronavirus disease 2019" (COVID-19), posing a threat to human health and public safety. S-RBD is a coronaviral protein that is essential for a coronavirus (CoV) to bind and penetrate into host cells. As a result, it has become a popular pharmacological target. The goal of this study was to find potential candidates for anti-coronavirus disease 2019 (COVID-19) drugs by targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-RBD with novel bioactive compounds and molecular interaction studies of 15,000 phytochemicals belonging to different flavonoid subgroups. A spike protein crystal structure attached to the ACE2 structure was obtained from the PDB database. A library of 15,000 phytochemicals was made by collecting compounds from different databases, such as the Zinc-database, PubChem-database, and MPD3-database. This library was docked against a receptor binding domain of a spike glycoprotein through the Molecular Operating Environment (MOE). The top drug candidates Phylloflavan, Milk thistle, Ilexin B and Isosilybin B, after virtual screening, were selected on the basis of the least binding score. Phylloflavan ranked as the top compound because of its least binding affinity score of -14.09 kcal/mol. In silico studies showed that all those compounds showed good activity and could be used as an immunological response with no bioavailability issues. Absorption, distribution, metabolism, excretion and a toxicological analysis were conducted through SwissADME. Stability and effectiveness of the docked complexes were elucidated by performing the 100 ns molecular dynamic simulation through the Desmond package.

Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions.

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

Phytochemicals: "A Small Defensive Advantage for Plants and Fungi; a Great Remedy for the Health of Mankind".

In the chronology of Biochemistry, as a new science that emerged in the mid-nineteenth century after its separation from Organic Chemistry and Physiology, its beginnings were characterized by an intense search and subsequent isolation and characterization of different organic compounds that were part of the chemical composition of living organisms [...].

Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations.

Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2.

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially appeared in Wuhan, China, in December 2019. Elderly individuals and those with comorbid conditions may be more vulnerable to this disease. Consequently, several research laboratories continue to focus on developing drugs to treat this infection because this disease has developed into a global pandemic with an extremely limited number of specific treatments available. Natural herbal remedies have long been used to treat illnesses in a variety of cultures. Modern medicine has achieved success due to the effectiveness of traditional medicines, which are derived from medicinal plants. The objective of this study was to determine whether components of natural origin from Iranian medicinal plants have an antiviral effect that can prevent humans from this coronavirus infection using the most reliable molecular docking method; in our case, we focused on the main protease (Mpro) and a receptor-binding domain (RBD). The results of molecular docking showed that among 169 molecules of natural origin from common Iranian medicinal plants, 20 molecules (chelidimerine, rutin, fumariline, catechin gallate, adlumidine, astragalin, somniferine, etc.) can be proposed as inhibitors against this coronavirus based on the binding free energy and type of interactions between these molecules and the studied proteins. Moreover, a molecular dynamics simulation study revealed that the chelidimerine-Mpro and somniferine-RBD complexes were stable for up to 50 ns below 0.5 nm. Our results provide valuable insights into this mechanism, which sheds light on future structure-based designs of high-potency inhibitors for SARS-CoV-2.

In silico screening of Allium cepa phytochemicals for their binding abilities to SARS and SARS-CoV-2 3C-like protease and COVID-19 human receptor ACE-2.

Corona virus SARS-CoV-2-induced viral disease (COVID-19) is a zoonotic disease that was initially transmitted from animals to humans. The virus surfaced towards the end of December 2019 in Wuhan, China where earlier SARS (Severe Acute Respiratory Syndrome) had also surfaced in 2003. Unlike SARS, SARS-CoV-2 (a close relative of the SARS virus) created a pandemic, and as of February 24 2021, caused 112,778,672 infections and 2,499,252 deaths world-wide. Despite the best efforts of scientists, no drugs against COVID-19 are yet in sight; five vaccines have received emergency approval in various countries, but it would be a difficult task to vaccinate twice the world population of 8 billion. The objective of the present study was to evaluate through in silico screening a number of phytochemicals in Allium cepa (onion) regarding their ability to bind to the main protease of COVID-19 known as the 3C-like protease or 3CLpro, (PDB ID: 6LU7), 3CLpro of SARS (PDB ID: 3M3V), and human angiotensin converting enzyme-2 (ACE-2), [PDB ID: 1R42], which functions as a receptor for entry of the virus into humans. Molecular docking (blind docking, that is docking not only against any target pocket) were done with the help of AutoDockVina. It was observed that of the twenty-two phytochemicals screened, twelve showed good binding affinities to the main protease of SARS-CoV-2. Surprisingly, the compounds also demonstrated good binding affinities to ACE-2. It is therefore very likely that the binding affinities shown by these compounds against both 3CLpro and ACE-2 merit further study for their potential use as therapeutic agents.

Tissue-Specific Accumulation and Isomerization of Valuable Phenylethanoid Glycosides from Plantago and Forsythia Plants.

A comparative phytochemical study on the phenylethanoid glycoside (PhEG) composition of the underground organs of three Plantago species (P. lanceolata, P. major, and P. media) and that of the fruit wall and seed parts of Forsythia suspensa and F. europaea fruits was performed. The leaves of these Forsythia species and six cultivars of the hybrid F. × intermedia were also analyzed, demonstrating the tissue-specific accumulation and decomposition of PhEGs. Our analyses confirmed the significance of selected tissues as new and abundant sources of these valuable natural compounds. The optimized heat treatment of tissues containing high amounts of the PhEG plantamajoside (PM) or forsythoside A (FA), which was performed in distilled water, resulted in their characteristic isomerizations. In addition to PM and FA, high amounts of the isomerization products could also be isolated after heat treatment. The isomerization mechanisms were elucidated by molecular modeling, and the structures of PhEGs were identified by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques, also confirming the possibility of discriminating regioisomeric PhEGs by tandem MS. The PhEGs showed no cytostatic activity in non-human primate Vero E6 cells, supporting their safe use as natural medicines and allowing their antiviral potency to be tested.

Caffeoylquinic acids: chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity.

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.

Computational hunting of natural active compounds as an alternative for Remdesivir to target RNA-dependent polymerase.

The hunt for potential lead/drug molecules from different resources, especially from natural resources, for possible treatment of COVID-19 is ongoing. Several compounds have already been identified, but only a few are good enough to show potential against the virus. Among the identified druggable target proteins of SARS-CoV-2, this study focuses on non-structural RNA-dependent RNA polymerase protein (RdRp), a well-known enzyme for both viral genome replication and viral mRNA synthesis, and is therefore considered to be the primary target. In this study, the virtual screening followed by an in-depth docking study of the Compounds Library found that natural compound Cyclocurcumin and Silybin B have strong interaction with RdRp and much better than the remdesivir with free binding energy and inhibition constant value as êzŒ-6.29 kcal/mol and 58.39 µMêzŒ, and êzŒ-7.93kcal/mol and 45.3 µMêzŒ, respectively. The finding indicated that the selected hits (Cyclocurcumin and Silybin B) could act as non-nucleotide anti-polymerase agents, and can be further optimized as a potential inhibitor of RdRp by benchwork experiments.

Repurposing of anticancer phytochemicals for identifying potential fusion inhibitor for SARS-CoV-2 using molecular docking and molecular dynamics (MD) simulations.

The viral particle, SARS-CoV-2 is responsible for causing the epidemic of Coronavirus disease 2019 (COVID-19). To combat this situation, numerous strategies are being thought for either creating its antidote, vaccine, or agents that can prevent its infection. For enabling research on these strategies, several target proteins are identified where, Spike (S) protein is of great potential. S-protein interacts with human angiotensin-converting-enzyme-2 (ACE2) for entering the cell. S-protein is a large protein and a portion of it designated as a receptor-binding domain (RBD) is the key region that interacts with ACE2, following to which the viral membrane fuses with the alveolar membrane to enter the human cell. The hypothesis is to identify molecules from the pool of anticancer phytochemicals as a lead possessing the ability to interact and mask the amino acids of RBD, making them unavailable to form associations with ACE2. Such a molecule is termed as 'fusion inhibitor'. We hypothesized to identify fusion inhibitors from the NPACT library of anticancer phytochemicals. For this, all the molecules from the NPACT were screened using molecular docking, the five top hits (Theaflavin, Ginkgetin, Ursolic acid, Silymarin and Spirosolane) were analyzed for essential Pharmacophore features and their ADMET profiles were studied following to which the best two hits were further analyzed for their interaction with RBD using Molecular Dynamics (MD) simulation. Binding free energy calculations were performed using MM/GBSA, proving these phytochemicals containing anticancer properties to serve as fusion inhibitors.Communicated by Ramaswamy H. Sarma.

Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme.

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.