ABSTRACT
COVID-19 has become a global challenge as there are very few treatment options available. This has proved to impact several physiological implications like immunological injury, myocardial infarction, micro-thrombus formation, neurological complications and multi-organ dysfunction. A combination therapy or a systems pharmacology approach can be adopted to fight against COVID-19. Here, we have proposed withaferin A as a system pharmacophore employing molecular docking strategy using AutoDock Vina and utilising different bioinformatics tools like PharmMapper, STRING database and PANTHER Pathway enrichment analysis. Docking results show that withaferin A exhibits a significant binding affinity with P2Y12 receptor, vitamin D-binding protein and annexin A5, hence implying that it could play a role in anti-thrombosis. Protein-protein interaction network showed its importance in innate immune system. Results also show that this molecule may have significant potential to modulate T cell activation too. Text mining results showed association of STAT3 with withaferin A. Our studies propose that withaferin A might also conquer the cytokine storm via STAT3. This study concludes that two strong targets of withaferin A, i.e. vitamin D-binding protein and STAT3, have been identified and that withaferin A can be used as a system pharmacophore for drug development in order to combat COVID-associated complicacies.
ABSTRACT
Withania somnifera (L.) Dunal belongs to the nightshade family Solanaceae and is commonly known as Ashwagandha. It is pharmacologically a significant medicinal plant of the Indian sub-continent, used in Ayurvedic and indigenous systems of medicine for more than 3,000 years. It is a rich reservoir of pharmaceutically bioactive constituents known as withanolides (a group of 300 naturally occurring C-28 steroidal lactones with an ergostane-based skeleton). Most of the biological activities of W. somnifera have been attributed to two key withanolides, namely, withaferin-A and withanolide-D. In addition, bioactive constituents such as withanosides, sitoindosides, steroidal lactones, and alkaloids are also present with a broad spectrum of therapeutic potential. Several research groups worldwide have discovered various molecular targets of W. somnifera, such as inhibiting the activation of nuclear factor kappa-B and promoting apoptosis of cancer cells. It also enhances dopaminergic D2 receptor activity (relief in Parkinson's disease). The active principles such as sitoindosides VII-X and withaferin-A possess free radical properties. Withanolide-D increases the radio sensitivity of human cancer cells via inhibiting deoxyribonucleic acid (DNA) damage to non-homologous end-joining repair (NHEJ) pathways. Withanolide-V may serve as a potential inhibitor against the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to combat COVID. The molecular docking studies revealed that the withanolide-A inhibits acetyl-cholinesterase in the brain, which could be a potential drug to treat Alzheimer's disease. Besides, withanolide-A reduces the expression of the N-methyl-D-aspartate (NMDA) receptor, which is responsible for memory loss in epileptic rats. This review demonstrates that W. somnifera is a rich source of withanolides and other bioactive constituents, which can be used as a safe drug for various chronic diseases due to the minimal side effects in various pre-clinical studies. These results are interesting and signify that more clinical trials should be conducted to prove the efficacy and other potential therapeutic effects in human settings.
ABSTRACT
The COVID-19 pandemic has been reported to have a high incidence of morbidity and mortality, resulting in a large number of human deaths over the world. Studies suggest the importance of natural phytocompounds as potential antiviral agents and hypothesize to use them as therapeutics against COVID-19 main protease target. This study aims to identify a therapeutically potential natural compound from the immunomodulatory plants to inhibit the progression of the SARS CoV-2 virus. A total 8 major constituents, from various immunomodulatory-medicinal plants used in ayurvedic kadha preparation i.e. Cinnamon species (Dalchini), Piper nigrum (Kaali Mirch), Ocimum tenuiflorum (Tulsi), Zingiber officinale (Ginger), and Withania somnifera (Ashwagandha), have been used to perform docking with drug target main protease structure (SARS-CoV-2 Mpro, PDB ID: 6LU7) followed by molecular simulations. The pharmacological evaluations such as drug likeliness and ADMET properties calculations and RMSD calculation for 50 ns time scale of molecular dynamics support the current investigation. This study provides evidence of comparative significance with possible computational validations for Withaferin A of W. somnifera (Ashwagandha) with therapeutic potential towards SARS-CoV-2 Mpro, as a lead molecule. This chapter shows the different properties of natural phytocompounds, which are available in ayurvedic kadha as described by the government of India. Further, it details about different computational softwares/pipelines (off lines/online, Free/commercial) used for molecular docking and dynamics analysis. The chapter explains all the associated steps/execution of programs with a demonstration of the antiviral capacity of the phytocompounds from immunomodulatory plants through the case study. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.
ABSTRACT
Despite the development and implementation of vaccinations, the SARS-CoV-2 pandemic has persisted for more than two years due to emerging novel variants. The new Omicron lineages are being intensively monitored by WHO. Scientists from all over the world have reported the recombinant variants, but their existence remains a point of contention. Currently, XE and BA.2 are the most common variants. Deltracron (a recombinant of Delta and Omicron) has been discovered in several investigations, although some experts believe the sequences that confirm its emergence are the product of contamination. This study looked at emerging variants including XD, XE, and XF, as well as various omicron lineages (BA.1, BA.2, BA.3, BA.4, and BA.5). Bioactive lipids including arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid have been highlighted as possible COVID-19 therapeutics. On the other hand, herbal remedies are supposed to be the key player in minimizing the fatality rates in India. Coronil, a herbal formulation was found to be the evidence-based medicine against SARS-CoV-2. The activity of the Coronil is attributed to its diverse bioactive composition which includes cordifolioside A, rosmarinic acid, magnoflorine, withaferin A, ursolic acid, withanone, palmatine, betulinic acid, withanoside IV, and withanoside V. The interaction of bioactive lipids, Coronil and SARS-CoV-2 emerging variants might be beneficial in the management of pandemic until the herd immunity is achieved.
ABSTRACT
Withania somnifera (L.) Dunal is a valuable plant of family Solanaceae, which is commonly known as Asgand in Unani system of medicine (Tibb-e-Unani). The plant is found throughout the drier parts of India and other parts of the world. The main drug component comprises of the roots that is used for its therapeutic actions either singly or as an ingredient in compound formulations. Asgand is well described in Unani classics as Musakkin (sedative), Muqawwi (tonic) Muhallil-e-waram (anti-inflammatory), Muaddil (alterative), and Muqawwi-e-Bah (aphrodisiac). In Unani system, it is prescribed for rheumatism, gynecological disorders, cough, hiccup dropsy, and as a sedative in cases of senile debility. Studies indicate that the pharmacological activities of the root and leaf are attributed to the presence of several alkaloids and steroidal lactones including withanine, somniferine, somnine, and somniferinine. Leaves contain a group of (nearly twelve) “Withanolides” including “Withaferin-A” with antibiotic and anti-tumor activity. Asgand possesses anti-inflammatory, antioxidant, anxiolytic, adaptogenic, memory enhancing, antiparkinsonian, and antitumor properties. Several other effects such as immuno-modulation, cardiovascular protection, hypolipidemic, antibacterial, and sexual behavior, tolerance have also been studied. In conventional Unani system, enhancing immunity with immune-boosters is one of the key approaches for prevention of disease and maintenance of health. An attempt has been made in this review to explore the various dimensions of the drug viz;morphological, pharmacological, chemical studies and more specifically the therapeutic actions, uses and Unani perspective of Asgand in the time of Covid-19.
ABSTRACT
In recent years, it has been reported that many herbal plants contain antiviral agents which combat a human disease that is caused by pathogenic viruses. The natural products which are obtained from plants as antiviral agents against viruses have gone through researches to check the efficacy and potentials of the herbal products in the prevention of viral disorders. On the basis of randomized controlled studies and in-vivo studies, and in-vitro studies, some agents are utilized all across the globe. Progressively numerous studies on therapy of antivirals have been increased. Though, efficacy remains disputable for antiviral drugs that are employed for viral disorders. The viral diseases are challenging for the health of people around the world cause significant increase in mortality and enhance crises. There are many synthetic antiviral drugs that have a large number of side effects and have narrow therapeutic window range, while in the other hand herbal formulations have minimized side effects. The advantages of herbal formulation over synthetic drugs encourage us to devise and expand new herbal moieties against the emerging viral infections. The medicinal plants contain phytochemicals that have antiviral properties. In this paper, the activity of antiviral agents from medicinal plants which have importance in Ayurveda, are discussed along with their source.
ABSTRACT
Oxidative stress is the state of imbalance between the production of reactive oxygen species (free radicals) in the biological system and the ability of the body to detoxify them resulting in increased accumulation of free radicals in the cells. This stress leads to weakening of the immune system thus leading to higher susceptibility to other infections as well. This also includes the weakening of the respiratory tract leading to increased susceptibility of viral infections as in the case of COVID-19. Treatment for any kind of abnormality requires the identification of the key target proteins and pathways that are being altered. Withania somnifera is being used in the traditional medicinal system to improve health and longevity thus creating a sense of mental as well as physical well being. The present study utilises network pharmacological approach to predict the potential oxidative stress targets of the three major withanolides: Withanolide A, withaferin A and withanone. Primarily, the targets of the individual withanolides were obtained from the Swiss target and DIGEP-pred databases and the GO terms and lead hits related to oxidative stress were retrieved from AMIGO2 database. Totally 40 correlative hits were obtained as anti stress targets of the withanolides, which were subjected to functional enrichment and protein-protein interaction analysis to study the enriched pathways underlying oxidative stress response. Further the eleven crucial targets of the four selected pathways were analysed using molecular docking analysis. A total of forty protein hits were obtained as oxidative stress targets of the withanolides. Further, the pathway enrichment of these forty target genes showed the AGE RAGE signalling pathway as highly enriched pathway. Therefore, the AGE RAGE signalling pathway along with its underlying pathways namely MAPK signalling pathway, FOXO pathway and PI3-AKT pathway were chosen among all the other enriched pathways. Further the molecular docking analysis of the eleven target proteins falling under these four pathways showed good docking scores of the withanolides with all the eleven targets with highest interaction against BCL2. From the above study, the biological targets and associated pathways of the withanolides have been retrieved. Thus the in silico approach undertaken in this study explores the role of the key withanolides in the antioxidant potential of the traditional medicinal plant Withania somnifera. © The authors.
ABSTRACT
Design and development of an effective compound to combat COVID-19 is clearly critical in the current circumstances. Therefore, it is of interest to document the molecular docking analysis data of the cellular receptor Glucose regulated protein 78 (GRP78) with Withaferin A from Withania somnifera in the context of COVID-19 pandemic for further consideration. Here, we report the optimal interaction features of withaferin A, artemisinin, curcumin and andrographolide with the GRP78 receptor having low binding energies (-8.7, -7.89, -6.21 and -6.17 kcal/mol respectively) in this report. In order to gain additional insights, the interaction pattern of compounds with SARS-CoV-2 main protease (Mpro) was studied.
ABSTRACT
The outbreak and continued spread of the novel coronavirus disease 2019 (COVID-19) is a preeminent global health threat that has resulted in the infection of over 11.5 million people worldwide. In addition, the pandemic has claimed the lives of over 530,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy, with cancer patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 due to the reported interference in viral S-protein to host receptor binding and its lack of effect on ACE2 expression in the lungs.