Phytocompounds as potential inhibitors of SARS-CoV-2 Mpro and PLpro through computational studies.

The inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) and papain-like protease (PLpro) prevents viral multiplications; these viral enzymes have been recognized as one of the most favorable targets for drug discovery against SARS-CoV-2. In the present study, we screened 225 phytocompounds present in 28 different Indian spices to identify compounds as potential inhibitors of SARS-CoV-2 Mpro and PLpro. Molecular docking, molecular dynamics simulation, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, and absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were done. Based on binding affinity, dynamics behavior, and binding free energies, the present study identifies pentaoxahexacyclo-dotriacontanonaen-trihydroxybenzoate derivative (PDT), rutin, and dihyroxy-oxan-phenyl-chromen-4-one derivative (DOC), luteolin-7-glucoside-4'-neohesperidoside as promising inhibitors of SARS-CoV-2 Mpro and PLpro, respectively.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies.

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Protective Effects of Diets Rich in Polyphenols in Cigarette Smoke (CS)-Induced Oxidative Damages and Associated Health Implications.

Cigarette smoking has been responsible for causing many life-threatening diseases such as pulmonary and cardiovascular diseases as well as lung cancer. One of the prominent health implications of cigarette smoking is the oxidative damage of cellular constituents, including proteins, lipids, and DNA. The oxidative damage is caused by reactive oxygen species (ROS, oxidants) present in the aqueous extract of cigarette smoke (CS). In recent years, there has been considerable interest in the potential health benefits of dietary polyphenols as natural antioxidant molecules. Epidemiological studies strongly suggest that long-term consumption of diets (fruits, vegetables, tea, and coffee) rich in polyphenols offer protective effects against the development of cancer, cardiovascular diseases, diabetes, osteoporosis, and neurodegenerative diseases. For instance, green tea has chemopreventive effects against CI-induced lung cancer. Tea might prevent CS-induced oxidative damages in diseases because tea polyphenols, such as catechin, EGCG, etc., have strong antioxidant properties. Moreover, apple polyphenols, including catechin and quercetin, provide protection against CS-induced acute lung injury such as chronic obstructive pulmonary disease (COPD). In CS-induced health problems, the antioxidant action is often accompanied by the anti-inflammatory effect of polyphenols. In this narrative review, the CS-induced oxidative damages and the associated health implications/pathological conditions (or diseases) and the role of diets rich in polyphenols and/or dietary polyphenolic compounds against various serious/chronic conditions of human health have been delineated.

Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects, Antioxidant Potentials and Mechanism(s) of Action.

Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans, stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables, spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent years, dietary polyphenols have gained significant interest among researchers due to their potential chemopreventive/protective functions in the maintenance of human health and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS) towards the prevention of OS-related pathological conditions or diseases. Pre-clinical and clinical evidence strongly suggest that long term consumption of diets rich in polyphenols offer protection against the development of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, diabetes, inflammatory disorders and infectious illness. Increased intake of foods containing polyphenols (for example, quercetin, epigallocatechin-3-gallate, resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial infections, and neurodegenerative diseases. It has been suggested that the antioxidant activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human diseases. In this narrative review, the biological/pharmacological significance of dietary polyphenols in the prevention of and/or protection against OS-induced major human diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus, cancer, inflammatory disorders and infectious diseases have been delineated. This review specifically focuses a current understanding on the dietary sources of polyphenols and their protective effects including mechanisms of action against various major human diseases.

Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations.

Severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic is the present worldwide health emergency. The global scientific community faces a significant challenge in developing targeted therapies to combat the SARS-CoV-2 infection. Computational approaches have been critical for identifying potential SARS-CoV-2 inhibitors in the face of limited resources and in this time of crisis. Main protease (Mpro) is an intriguing drug target because it processes the polyproteins required for SARS-CoV-2 replication. The application of Ayurvedic knowledge from traditional Indian systems of medicine may be a promising strategy to develop potential inhibitor for different target proteins of SARS-CoV-2. With this endeavor, we docked bioactive molecules from Triphala, an Ayurvedic formulation, against Mpro followed by molecular dynamics (MD) simulation (100 ns) to investigate their inhibitory potential against SARS-CoV-2. The top four best docked molecules (terflavin A, chebulagic acid, chebulinic acid, and corilagin) were selected for MD simulation study and the results obtained were compared to native ligand X77. From docking and MD simulation studies, the selected molecules showed promising binding affinity with the formation of stable complexes at the active binding pocket of Mpro and exhibited negative binding energy during MM-PBSA calculations, indication their strong binding affinity with the target protein. The identified bioactive molecules were further analyzed for drug-likeness by Lipinski's filter, ADMET and toxicity studies. Computational (in silico) investigations identified terflavin A, chebulagic acid, chebulinic acid, and corilagin from Triphala formulation as promising inhibitors of SARS-CoV-2 Mpro, suggesting experimental (in vitro/in vivo) studies to further explore their inhibitory mechanisms.

Coronavirus Disease-2019 (COVID-19): An Updated Review.

The current outbreak of novel Coronavirus Disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major pandemic situation and a catastrophe for humans. COVID-19 is a severe infectious disease particularly of the respiratory system characterized by fatal complications such as severe acute respiratory distress syndrome (SARS), pneumonia, cardiac arrhythmia, kidney failure/ multiple organ failure and even death. Since its discovery, the SARS-CoV-2 has spread across 213 countries or territories, causing more than 8.5 million people with a rising death toll over 5.5 million people (as of June 2020, WHO). In fact, the current looming crisis of COVID-19 has become an increasingly serious concern to public health. It has affected lives of millions of people with severe impact on health systems and economies globally. Since there are no specific drugs and/or vaccines available so far, combating COVID-19 remains to be a major challenging task. Therefore, development of potential and effective treatment regimens (prophylactic/therapeutic) is urgently required which could resolve the issue. In this review, we summarize the current knowledge about the coronavirus, disease epidemiology, clinical manifestations and risk factors, replication of the virus, pathophysiology and host immune responses of SARS-CoV-2 infection. The therapeutic interventions and prophylactic measures along with precautionary measures are the frontline approaches that could be undertaken in order to control and prevent the spread of the deadly and highly contagious COVID-19 are also detailed herein.