Screening for Potential Traditional Herbal Inhibitors Against 3-Chymo-trypsin-like Main Protease (3CLpro) from Four Different Coronaviruses: An in silico Approach

Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective(s): The 3-chymotrypsin-like main protease (3CLpro), also referred to as the "Achilles' heel" of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus' life cycle. The objective of the study was to screen and identify broad--spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Method(s): Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Result(s): Our study shows that natural phytoconstituents in Triphala (a blend of Emblica officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phyto-constituents' binding interactions clearly showed strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion(s): This study provides a valuable scaffold for repurposing traditional herbs with anti--CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.Copyright © 2021 Bentham Science Publishers.

Herbal and Ayurvedic Plants as Remedial Approach for Viral Diseases with Focus on COVID-19: A Narrative Review

Background: Infectious diseases have posed a major threat to human survival for centu-ries and can devastate entire populations. Recently, the global outbreak of COVID-19 has increased exponentially, affecting more than 200 countries and millions of lives since the fall of 2019, largely due to the ineffectiveness of existing antiviral therapies. WHO announced it a public health emer-gency of international concern. A significant waiting period in antiviral therapy hindered by the rapid evolution of severe acute respiratory syndrome-coronavirus-2 aggravated the situation ensuing imposition of strict laws (e.g., communal dissociation, international travel restrictions, and mainte-nance of hygiene) that would help in inhibiting further outspread of COVID-19. Ayurveda system of medicine offers a holistic approach to the COVID-19 pandemic. Objective(s): This review aims to highlight the potential of medicinal herbs and Ayurvedic drugs as the remedial approach for viral diseases, such as COVID-19. Method(s): We reviewed the literature from journal publication websites and electronic databases, such as Bentham, Science Direct, Pub Med, Scopus, USFDA, etc. Result(s): The drugs used in the traditional system of medicine have the potential to prevent and cure the infected patient. Ayurvedic therapies are known for regulating immunity and rejuvenation properties that behold much promise in the management of COVID-19 disease. Government of India, Ministry of AYUSH recommends some precautionary fitness measures and an increase in immunity with special reference to respiratory health. Conclusion(s): While there is no medication for COVID-19 as of now, taking preventive measures and boosting body immunity is highly recommended. A number of medicinal plants that play an im-portant role in revitalizing the immune system are easily accessible in home remedies.Copyright © 2023 Bentham Science Publishers.

Molecular insights into the in silico discovery of corilagin from Terminalia chebula as a potential dual inhibitor of SARS-CoV-2 structural proteins.

The spike (S) glycoprotein and nucleocapsid (N) proteins are the crucial pathogenic proteins of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus during its interaction with the host. Even FDA-approved drugs like dexamethasone and grazoprevir are not able to curb the viral progression inside the host and are reported with adverse effects on body metabolism. In this context, we aim to report corilagin a novel, potential dual inhibitor of S and N proteins from Terminalia chebula. The bioactive compounds of T. chebula were subjected to a series of computational investigations including molecular docking simulations, molecular dynamics (MD) simulations, binding free energy calculations, and PASS pharmacological analysis. The results obtained from these studies revealed that corilagin was highly interactive with the S (-8.9 kcal/mol) and N (-9.2 kcal/mol) proteins, thereby showing dual inhibition activity. It was also found to be stable enough to induce biological activity inside the inhibitor binding pocket of the target enzymes throughout the dynamics simulation run for 100 ns. This is also confirmed by the changes in the protein conformations, evaluated using free energy landscapes. Outcomes from this investigation identify corilagin as the lead potential dual inhibitor of S and N proteins of SARS-CoV-2, which could be taken for biological studies in near future.Communicated by Ramaswamy H. Sarma.

Molecular docking studies of phytochemicals from Terminalia chebula for identification of potential multi-target inhibitors of SARS-CoV-2 proteins.

Background: The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a global pandemic claiming more than 6 million lives worldwide as of 16 March 2022. Till date, no medicine has been developed which is proved to have 100% efficiency in combating against this deadly disease. We focussed on ayurvedic medicines to identify drug-like candidates for treatment and management of COVID-19. Among all ayurvedic medicines, we were interested in Terminalia chebula (T. chebula), as it is known to have antibacterial, antifungal, antiviral, antioxidant and anti-inflammatory properties. Objectives: In this study, we evaluated potential inhibitory effects of phytochemicals from T. chebula against eight structural and functional proteins of SARS-CoV-2. Material and methods: We performed blind molecular docking studies using fifteen phytochemicals from T. chebula against the proteins of SARS-CoV-2. The three-dimensional proteins structures were analysed and potential drug-binding sites were identified. The drug-likeness properties of the ligands were assessed as well. Results: Analysing the docking results by comparing Atomic Contact Energy (ACE) and intermolecular interactions along with assessment of ADME/T properties identified 1,3,6-Trigalloyl glucose (-332.14 ± 55.74 kcal/mol), Beta-Sitosterol (-324.75 ± 36.98 kcal/mol) and Daucosterol (-335.67 ± 104.79 kcal/mol) as most promising candidates which exhibit significantly high inhibition efficiency against all eight protein targets. Conclusions: We believe that our study has the potential to help the scientific communities to develop multi-target drugs from T. chebula to combat against the deadly pathogen of COVID-19, with the support of extensive wet lab analysis.

Anti-Obesity Siddha Medicinal Plants-A Preclinical Review

Obesity is a complex multi factorial preventable disease affecting all age groups of both the sexes. Now one third of world’s population is overweight or obese. From 1980 the world-wide prevalence of obesity has become doubled. Overweight and obesity were the 5th foremost causes of death globally. Obesity is associated with many co morbid diseases. Prevalence of obesity with co morbidities is on big alarm throughout the world. Recently in COVID-19 pandemic most of the obese people get affected due to the co morbidities and reduced immunity. The anti-obesity properties of medicinal plants were known from ancient times in traditional Siddha medicine some thousand years ago. Many Siddha medicinal plants showed anti-obesity activities that can be utilized in the management of obesity, through which the complications of obesity can be prevented. Most researches explored the anti-obesity potentials of medicinal plants. Terminalia chebula, Phyllanthus niruri, zingiber officinale, Piper longum, Curcuma longa, Elettaria cardamomum, Cuminum cyminum, Picrorhiza kurroa, Ipomea turpethum, Tinospora cordifolia, Michelia champaka are some medicinal plants possess anti-obesity properties that had been indicated in Siddha classical text. The objective of this review is to validate the anti-obesity potentials of Siddha medicinal plants scientifically through various research reports. Due to the presence of Phyto compounds like phenols, flavonoids, terpenoids, alkaloids, anti-oxidants these medicinal plants revealed anti-obesity activities and its anti-obesity mechanism had been proven scientifically through various animal experimental studies collected from many research articles. Modern anti-obesity drugs produce numerous side effects. Regular consumption of Siddha anti-obesity medicinal plants, in the prescribed dose and duration, can induce gradual and sustainable weight loss effectively. Furthermore, in future, there is a need for the development of standardized, safe and effective anti-obesity drugs from medicinal plants and highly economical too. Hence eventually exploration of anti-obesity Siddha medicinal plants will lead to safe and effective treatment for obesity.

Identification of Alkaloids from Terminalia chebula as Potent SARS- CoV-2 Main Protease Inhibitors: An In Silico Perspective.

Natural compounds in medicinal plants are best remedies for different diseases and are important to develop new drugs. This work was dedicated to understand the role of different natural compounds of Terminalia Chebula, a well-known herbal plant, in the treating of Covid 19. In this article, we have investigated interactions of such natural compounds from Terminalia Chebula with the main protease (Mpro) of the SARS-CoV-2, which is a key component for cleavage of viral polyprotein, and an important target for the development of drugs towards COVID-19. We have performed molecular docking study on 22 different molecules of Terminalia Chebula and proposed that 7 of the natural compounds (triterpenoids and sterols) interacts with a comparable or stronger interactions than the inhibitor N3. Molecular dynamics simulations (100 ns) revealed that 7 Mpro-Terminalia Chebula complexes are stable, conformationally less fluctuated, slightly less compact, and marginally expanded than ligand-free conformation of Mpro. The intermolecular H-bonding and detailed MM/PBSA and MM-GBSA analysis showed Daucosterol interaction to be the most strong, whereas comparable interactions were observed for Arjunetin, Maslinic acid, and Bellericoside. Our study suggested that these natural compounds can act as potent Mpro inhibitors for SARS-CoV-2, and may evolve as promising anti-COVID-19 drugs in the near future.