In Silico Insight into the Inhibitory Effects of Active Antidiabetic Compounds from Medicinal Plants Against SARS-CoV-2 Replication and Post-translational Modification

Background: The recent reemergence of the coronavirus (COVID-19) caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has prompted the search for effective treatments in the forms of drugs and vaccines. Aim(s): In this regard, we performed an in silico study on 39 active antidiabetic compounds of medicinal plants to provide insight into their possible inhibitory potentials against SARS-CoV-2 replications and post-translational modifications. Top 12 active antidiabetic compounds with potential for dual inhibition of the replications and post-translational modifications of SARS-CoV-2 were ana-lyzed. Result(s): Boswellic acids, celastrol, rutin, sanguinarine, silymarin, and withanolides expressed binding energy for 3-chymotrypsin-like protease (3CLpro) (-8.0 to-8.9 Kcal/mol), papain-like protease (PLpro) (-9.1 to-10.2 Kcal/mol), and RNA-dependent RNA polymerase (RdRp) (-8.5 to-9.1 Kcal/-mol) which were higher than the reference drugs (Lopinavir and Remdesivir) used in this study. Sanguinarine, silymarin, and withanolides are the most druggable phytochemicals among other phy-tochemicals as they follow Lipinski's rule of five analyses. Sanguinarine, silymarin, and withano-lides expressed moderate solubility with no hepatotoxicity, while silymarin and withanolides could not permeate the blood-brain barrier and showed no Salmonella typhimurium reverse mutation as-say (AMES) toxicity, unlike sanguinarine from the predictive absorption, distribution, metabolism, elimination, and toxicity (ADMET) studies. Conclusion(s): Sanguinarine, silymarin, and withanolides could be proposed for further experimental studies for their development as possible phytotherapy for the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

In silico investigation and identification of bioactive compounds from medicinal plants as potential inhibitors against SARS-CoV-2 cellular entry

The present study conducted an in silico investigation and identifications of bioactive compounds from medicinal plants against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cellular entry. Thirty nine (39) bioactive compounds with evidence of in vitro or in vivo antidiabetic activities from medicinal plants were utilized in order to provide insight about their possible inhibitory potentials against SARS-CoV-2 cellular entry. Results from this study showed that silymarin, sanguinarine, withanolides, boswellic acids, fisetin, celastrol, neferine, ursolic acid, rutin, gambogic acid, quercetin, and luteolin expressed multiple binding capacity against nucleocapsid dimerization domain (−10.7 to −8.4kcal/mol), spike's protein binding domain (−10.0 to −8.1kcal/mol), and spike receptor-binding domain (−10.8 to −9.0kcal/mol) compared to lopinavir and remdesivir which were used as reference compounds in the study. However, withanolides, fisetin, luteolin, sanguinarine, and silymarin are most druggable phytochemicals as they obey the Lipinski's rule of five analyses with no signs of in silico predictory toxicity. Thus, they are recommended for further studies for the development of phytotherapy formulation to combat SARS-CoV-2 disease. © 2022 Elsevier Inc. All rights reserved.

In silico insight into the interaction of 4-aminoquinolines with selected SARS-CoV-2 structural and nonstructural proteins

The development of efficacious therapeutic agents with relatively low or no level of toxicity was necessitated due to the reemergence of coronavirus. The present study investigated the inhibitory potentials of 4-aminoquinolines (amopyroquine, mefloquine, amodiaquine, bispyroquine, quinine, chloroquine, hydroxychloroquine, chloroquine hydrochloride, chloroquine sulfate, cycloquine, and quinacrine) against selected structural and nonstructural proteins of SARS-CoV-2. The 4-aminoquinolines with higher binding affinities were selected for physicochemical properties, absorption, distribution, metabolism, and excretion (ADME) analysis. The binding energies were computed with Autodock vina screening software while physicochemical properties and ADME parameters were predicted through SwissADME server. Amopyroquine, mefloquine, bispyroquine, and quinine had the highest binding affinities with the amino acids in the pocket of the SARS-CoV-2 structural proteins (envelope, membrane, nucleocapsid, and spike) and nonstructural proteins (3-chymotrypsin-like protease, papain-like protease, and RNA-dependent RNA polymerase) compared with chloroquine and other 4-aminoquinolines used in this study. In addition, the pharmacokinetics and physicochemical parameters revealed that amopyroquine, mefloquine, bispyroquine, and quinine demonstrated good drug-like properties with relatively low toxic effects. The data from this study provide evidence that some of the 4-aminoquinolines can be repurposed and further developed as therapeutic agents with potentials to inhibit coronavirus cellular entry and replication. © 2022 Elsevier Inc. All rights reserved.

Dexamethasone

The corticosteroid drug “dexamethasone” has been in use since 1960s for reducing inflammation in a variety of conditions such as certain cancers and other inflammatory disorders. It is an affordable agent and currently off-patent in most countries and listed in multiple formulations since 1977 in the World Health Organization model list of essential medicines. The cytokines production and damaging effect has been limited through the use of dexamethasone and this will also block B cells from antibodies production and inhibit the T cell's protective function potential leading to elevated viral load in the plasma that persists for longer time after a patient survives SARS. In addition, dexamethasone would chunk the macrophages from clearing the resultant nosocomial infections. Thus, dexamethasone may be valuable for the immediate relief in severe cases of COVID-19, but could be dangerous on the long run as the body will be barred from producing protective antibodies in addition to the persistence of the virus. © 2022 Elsevier Inc. All rights reserved.

Pathogenesis and mutagenesis of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is a highly infectious disease characterized by higher leukocyte numbers, acute respiratory distress, and elevated levels of plasma proinflammatory cytokines. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, begins its pathogenesis by the binding of the virus to the host's angiotensin-converting enzyme 2 (ACE-2) receptor and then replication. The various replicated viruses then reinfect other cells and organs with ACE-2 receptor and further wreak havoc and could later result in multisystem organ failure. Presently, efforts are on the way to develop vaccines and drugs for this virus. But the current spike in COVID-19 cases linked to mutation in the virus genome and those of its enzymes is a cause of concern. Studies conducted by some authors have identified 6 major clads (basal, D614G, L84S, L3606F, D448del, and G392D), out of which D614G (a G-to-A base change at position 23403 in the Wuhan reference strain) was found to be the most reoccurring clad. This chapter examines all of these. © 2022 Elsevier Inc. All rights reserved.