Biomedical and Antioxidant Potentialities in Chilli: Perspectives and Way Forward.

Worldwide, since ages and nowadays, traditional medicine is well known, owing to its biodiversity, which immensely contributed to the advancement and development of complementary and alternative medicines. There is a wide range of spices, herbs, and trees known for their medicinal uses. Chilli peppers, a vegetable cum spice crop, are bestowed with natural bioactive compounds, flavonoids, capsaicinoids, phytochemicals, phytonutrients, and pharmacologically active compounds with potential health benefits. Such compounds manifest their functionality over solo-treatment by operating in synergy and consortium. Co-action of these compounds and nutrients make them potentially effective against coagulation, obesity, diabetes, inflammation, dreadful diseases, such as cancer, and microbial diseases, alongside having good anti-oxidants with scavenging ability to free radicals and oxygen. In recent times, capsaicinoids especially capsaicin can ameliorate important viral diseases, such as SARS-CoV-2. In addition, capsaicin provides an ability to chilli peppers to ramify as topical agents in pain-relief and also benefitting man as a potential effective anesthetic agent. Such phytochemicals involved not only make them useful and a much economical substitute to wonder/artificial drugs but can be exploited as obscene drugs for the production of novel stuffs. The responsibility of the TRPV1 receptor in association with capsaicin in mitigating chronic diseases has also been justified in this study. Nonetheless, medicinal studies pertaining to consumption of chilli peppers are limited and demand confirmation of the findings from animal studies. In this artifact, an effort has been made to address in an accessible format the nutritional and biomedical perspectives of chilli pepper, which could precisely upgrade and enrich our pharmaceutical industries towards human well-being.

Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm.

Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.

The impact of mucormycosis (black fungus) on SARS-CoV-2-infected patients: at a glance.

The emergence of various diseases during the COVID-19 pandemic made health workers more attentive, and one of the new pathogens is the black fungus (mucormycosis). As a result, millions of lives have already been lost. As a result of the mutation, the virus is constantly changing its traits, including the rate of disease transmission, virulence, pathogenesis, and clinical signs. A recent analysis revealed that some COVID-19 patients were also coinfected with a fungal disease called mucormycosis (black fungus). India has already categorized the COVID-19 patient black fungus outbreak as an epidemic. Only a few reports are observed in other countries. The immune system is weakened by COVID-19 medication, rendering it more prone to illnesses like black fungus (mucormycosis). COVID-19, which is caused by a B.1.617 strain of the SARS-CoV-2 virus, has been circulating in India since April 2021. Mucormycosis is a rare fungal infection induced by exposure to a fungus called mucormycete. The most typically implicated genera are Mucor rhyzuprhizopusdia and Cunninghamella. Mucormycosis is also known as zygomycosis. The main causes of infection are soil, dumping sites, ancient building walls, and other sources of infection (reservoir words "mucormycosis" and "zygomycosis" are occasionally interchanged). Zygomycota, on the other hand, has been identified as polyphyletic and is not currently included in fungal classification systems; also, zygomycosis includes Entomophthorales, but mucormycosis does not. This current review will be focused on the etiology and virulence factors of COVID-19/mucormycosis coinfections in COVID-19-associated mucormycosis patients, as well as their prevalence, diagnosis, and treatment.

Correction: Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro.

[This corrects the article DOI: 10.1039/D0RA06038K.].

Natural therapeutics and nutraceuticals for lung diseases: Traditional significance, phytochemistry, and pharmacology.

BACKGROUND: Lung diseases including chronic obstructive pulmonary disease (COPD), infections like influenza, acute respiratory distress syndrome (ARDS), asthma and pneumonia lung cancer (LC) are common causes of sickness and death worldwide due to their remoteness, cold and harsh climatic conditions, and inaccessible health care facilities. PURPOSE: Many drugs have already been proposed for the treatment of lung diseases. Few of them are in clinical trials and have the potential to cure infectious diseases. Plant extracts or herbal products have been extensively used as Traditional Chinese Medicine (TCM) and Indian Ayurveda. Moreover, it has been involved in the inhibition of certain genes/protiens effects to promote regulation of signaling pathways. Natural remedies have been scientifically proven with remarkable bioactivities and are considered a cheap and safe source for lung disease. METHODS: This comprehensive review highlighted the literature about traditional plants and their metabolites with their applications for the treatment of lung diseases through experimental models in humans. Natural drugs information and mode of mechanism have been studied through the literature retrieved by Google Scholar, ScienceDirect, SciFinder, Scopus and Medline PubMed resources against lung diseases. RESULTS: In vitro, in vivo and computational studies have been explained for natural metabolites derived from plants (like flavonoids, alkaloids, and terpenoids) against different types of lung diseases. Probiotics have also been biologically active therapeutics against cancer, anti-inflammation, antiplatelet, antiviral, and antioxidants associated with lung diseases. CONCLUSION: The results of the mentioned natural metabolites repurposed for different lung diseases especially for SARS-CoV-2 should be evaluated more by advance computational applications, experimental models in the biological system, also need to be validated by clinical trials so that we may be able to retrieve potential drugs for most challenging lung diseases especially SARS-CoV-2.

Repurposing of anisomycin and oleandomycin as a potential anti-(SARS-CoV-2) virus targeting key enzymes using virtual computational approaches.

Despite the accelerated emerging of vaccines, development against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) drugs discovery is still in demand. Repurposing the existing drugs is an ideal time/cost-effective strategy to tackle the clinical impact of SARS CoV-2. Thereby, the present study is a promising strategy that proposes the repurposing of approved drugs against pivotal proteins that are responsible for the viral propagation of SARS-CoV-2 virus Angiotensin-converting enzyme-2 (ACE2; 2AJF), 3CL-protease: main protease (6LU7), Papain-like protease (6W9C), Receptor Binding Domain of Spike protein (6VW1), Transmembrane protease serine 2 (TMPRSS-2; 5AFW) and Furin (5MIM) by in silico methods. Molecular docking results were analyzed based on the binding energy and active site interactions accomplished with pharmacokinetic analysis. It was observed that both anisomycin and oleandomycin bind to all selected target proteins with good binding energy, achieving the most favorable interactions. Considering the results of binding affinity, pharmacokinetics and toxicity of anisomycin and oleandomycin, it is proposed that they can act as potential drugs against the SARS CoV-2 infection. Further clinical testing of the reported drugs is essential for their use in the treatment of SARS CoV-2 infection.

Tripeptides from Allium subhirsitum L. extracts: Pharmacokinetics properties, toxicity prediction and in silico study against SARS-CoV-2 enzymes and pro-inflammatory proteins.

Developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities is urgently needed to combat emerging human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum L. (Hairy garlic) extracts identified through HR-LC/MS analysis that could potentially hinder the multiplication cycle of SARS-CoV-2 via molecular docking study. The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7 kcal/mol towards hACE2, (Thr-Leu-Trp) of -10.3 kcal/mol and (Gln-Phe-Tyr) of -9.8 kcal/mol against furin. Additionally, the identified peptides show strong interactions with the targeted and pro-inflammatory ranging from -8.1 to -10.5 kcal/mol for NF-κB-inducing kinase (NIK), from -8.2 to -10 kcal/mol for phospholipase A2 (PLA2), from -8.0 to -10.7 kcal/mol for interleukin-1 receptor-associated kinase 4 (IRAK-4), and from -8.6 to -11.6 kcal/mol for the cyclooxygenase 2 (COX2) with Gln-Phe-Tyr model seems to be the most prominent. Results from pharmacophore, drug-likeness and ADMET prediction analyses clearly evidenced the usability of the peptides to be developed as an effective drug, beneficial for COVID-19 treatment.

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations.

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro.

Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (Mpro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski's filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as Mpro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.

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.

Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and Other Coronaviruses: A Genome-wide Comparative Annotation and Analysis.

Novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) causes mild to severe respiratory illness. The early symptoms may be fever, dry cough, sour throat, and difficulty in breathing which may lead to death in severe cases. Compared to previous outbreaks like SARS-CoV and Middle East Respiratory Syndrome (MERS), SARS-CoV2 disease (COVID-19) outbreak has been much distressing due to its high rate of infection but low infection fatality rate (IFR) with 1.4% around the world. World Health Organization (WHO) has declared (COVID-19) a pandemic on March 11, 2020. In the month of January 2020, the whole genome of SARS-CoV2 was sequenced which made work easy for researchers to develop diagnostic kits and to carry out drug repurposing to effectively alleviate the pandemic situation in the world. Now, it is important to understand why this virus has high rate of infectivity or is there any factor involved at the genome level which actually facilitates this virus infection globally? In this study, we have extensively analyzed the whole genomes of different coronaviruses infecting humans and animals in different geographical locations around the world. The main aim of the study is to identify the similarity and the mutational adaptation of the coronaviruses from different host and geographical locations to the SARS-CoV2 and provide a better strategy to understand the mutational rate for specific target-based drug designing. This study is focused to every annotation in a comparative manner which includes SNPs, repeat analysis with the different categorization of the short-sequence repeats and long-sequence repeats, different UTR's, transcriptional factors, and the predicted matured peptides with the specific length and positions on the genomes. The extensive analysis on SNPs revealed that Wuhan SARS-CoV2 and Indian SARS-CoV2 are having only eight SNPs. Collectively, phylogenetic analysis, repeat analysis, and the polymorphism revealed the genomic conserveness within the SARS-CoV2 and few other coronaviruses with very less mutational chances and the huge distance and mutations from the few other species.

Identification of Persuasive Antiviral Natural Compounds for COVID-19 by Targeting Endoribonuclease NSP15: A Structural-Bioinformatics Approach.

SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.

Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro.

Novel coronavirus (CoV) is the primary etiological virus responsible for the pandemic that started in Wuhan in 2019-2020. This viral disease is extremely prevalent and has spread around the world. Preventive steps are restricted social contact and isolation of the sick individual to avoid person-to-person transmission. There is currently no cure available for the disease and the search for novel medications or successful therapeutics is intensive, time-consuming, and laborious. An effective approach in managing this pandemic is to develop therapeutically active drugs by repurposing or repositioning existing drugs or active molecules. In this work, we developed a feature-based pharmacophore model using reported compounds that inhibit SARS-CoV-2. This model was validated and used to screen the library of 565 FDA-approved drugs against the viral main protease (Mpro), resulting in 66 drugs interacting with Mpro with higher binding scores in docking experiments than drugs previously reported for the target diseases. The study identified drugs from many important classes, viz. D2 receptor antagonist, HMG-CoA inhibitors, HIV reverse transcriptase and protease inhibitors, anticancer agents and folate inhibitors, which can potentially interact with and inhibit the SARS-CoV-2 Mpro. This validated approach may help in finding the urgently needed drugs for the SARS-CoV-2 pandemic with infinitesimal chances of failure.