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1.
Biomed Pharmacother ; 147: 112658, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1641135

ABSTRACT

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Phytochemicals/therapeutic use , Phytotherapy , Alkaloids/therapeutic use , Benzaldehydes/therapeutic use , Benzoquinones/therapeutic use , Caffeic Acids/therapeutic use , Cinnamates/therapeutic use , Depsides/therapeutic use , Ellagic Acid/therapeutic use , Humans , Quercetin/therapeutic use , SARS-CoV-2 , Thymol/therapeutic use , Triterpenes/therapeutic use
2.
Molecules ; 26(18)2021 Sep 09.
Article in English | MEDLINE | ID: covidwho-1410348

ABSTRACT

Metabolic syndrome (MetS) is a constellation of risk factors that may lead to a more sinister disease. Raised blood pressure, dyslipidemia in the form of elevated triglycerides and lowered high-density lipoprotein cholesterol, raised fasting glucose, and central obesity are the risk factors that could lead to full-blown diabetes, heart disease, and many others. With increasing sedentary lifestyles, coupled with the current COVID-19 pandemic, the numbers of people affected with MetS will be expected to grow in the coming years. While keeping these factors checked with the polypharmacy available currently, there is no single strategy that can halt or minimize the effect of MetS to patients. This opens the door for a more natural way of controlling the disease. Caffeic acid (CA) is a phytonutrient belonging to the flavonoids that can be found in abundance in plants, fruits, and vegetables. CA possesses a wide range of beneficial properties from antioxidant, immunomodulatory, antimicrobial, neuroprotective, antianxiolytic, antiproliferative, and anti-inflammatory activities. This review discusses the current discovery of the effect of CA against MetS.


Subject(s)
Caffeic Acids/pharmacology , Metabolic Syndrome/drug therapy , Animals , Humans
3.
Arch Microbiol ; 203(6): 3557-3564, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1216209

ABSTRACT

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE-II, is a type I integral membrane protein of 805 amino acids that contains 1 HEXXH-E zinc binding consensus sequence. ACE-II has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). In this study, the potential of some flavonoids presents in propolis to bind to ACE-II receptors was calculated with in silico. Binding constants of ten flavonoids, caffeic acid, caffeic acid phenethyl ester, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin and quercetin were measured using the AutoDock 4.2 molecular docking program. And also, these binding constants were compared to reference ligand of MLN-4760. The results are shown that rutin has the best inhibition potentials among the studied molecules with high binding energy - 8.04 kcal/mol, and it is followed by myricetin, quercetin, caffeic acid phenethyl ester and hesperetin. However, the reference molecule has binding energy of - 7.24 kcal/mol. In conclusion, the high potential of flavonoids in ethanolic propolis extracts to bind to ACE-II receptors indicates that this natural bee product has high potential for COVID-19 treatment, but this needs to be supported by experimental studies.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19/drug therapy , Propolis/pharmacology , Animals , Bees , Caffeic Acids , Flavanones , Flavonoids , Hesperidin , Humans , Luteolin , Molecular Docking Simulation , Phenylethyl Alcohol/analogs & derivatives , Plant Extracts , Quercetin , Rutin
4.
Biotechnol Appl Biochem ; 69(2): 469-478, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1083974

ABSTRACT

Para-hydroxybenzoic acid (PHBA) has great potential in biological applications due to its putative antiviral activity against SARS-CoV-2 and its antimicrobial activity in the face of the radically increasing number of multidrug-resistant pathogens. This is in addition to its antimutagenic, anti-inflammatory, antioxidant, hypoglycemic, antiestrogenic, and antiplatelet aggregating activities. In this study, an approximate sixfold increase in the production of PHBA was achieved via biotransformation of caffeic acid by Candida albicans. The improvement was performed in two steps: first, through mutation by gamma irradiation (5 KGy dose), resulting in the recovery of a mutant (CI-24), which produced approximately triple the amount of PHBA produced by the wild-type isolate. Then, biotransformation by this mutant was further optimized via response surface methodology model-based optimization. The maximum PHBA production (7.47 mg/mL) was obtained in a fermentation medium composed of 1% w/v yeast extract as a nitrogen source, with an initial pH of 6.6, incubated at 28 °C at an agitation rate of 250 rpm. To further enhance the performance and economics of the process, cells of the CI-24 mutant were immobilized in calcium alginate beads and could retain an equivalent biotransformation capacity after three successive biotransformation cycles.


Subject(s)
COVID-19 , Candida albicans , Biotransformation , Caffeic Acids , Fermentation , Parabens , SARS-CoV-2
5.
J Med Virol ; 93(5): 3143-3151, 2021 05.
Article in English | MEDLINE | ID: covidwho-1082050

ABSTRACT

Since December 2019, the new coronavirus (also known as severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2, 2019-nCoV])-induced disease, COVID-19, has spread rapidly worldwide. Studies have reported that the traditional Chinese medicine Salvia miltiorrhiza possesses remarkable antiviral properties; however, the anti-coronaviral activity of its main components, salvianolic acid A (SAA), salvianolic acid B (SAB), and salvianolic acid C (SAC) is still debated. In this study, we used Cell Counting Kit-8 staining and flow cytometry to evaluate the toxicity of SAA, SAB, and SAC on ACE2 (angiotensin-converting enzyme 2) high-expressing HEK293T cells (ACE2h cells). We found that SAA, SAB, and SAC had a minor effect on the viability of ACE2h cells at concentrations below 100 µM. We further evaluated the binding capacity of SAA, SAB, and SAC to ACE2 and the spike protein of 2019-nCoV using molecular docking and surface plasmon resonance. They could bind to the receptor-binding domain (RBD) of the 2019-nCoV with a binding constant (KD ) of (3.82 ± 0.43) e-6 M, (5.15 ± 0.64)e-7 M, and (2.19 ± 0.14)e-6 M; and bind to ACE2 with KD (4.08 ± 0.61)e-7 M, (2.95 ± 0.78)e-7 M, and (7.32 ± 0.42)e-7 M, respectively. As a result, SAA, SAB, and SAC were determined to inhibit the entry of 2019-nCoV Spike pseudovirus with an EC50 of 11.31, 6.22, and 10.14 µM on ACE2h cells, respectively. In conclusion, our study revealed that three Salvianolic acids can inhibit the entry of 2019-nCoV spike pseudovirus into ACE2h cells by binding to the RBD of the 2019-nCoV spike protein and ACE2 protein.


Subject(s)
Alkenes/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Benzofurans/pharmacology , Caffeic Acids/pharmacology , Lactates/pharmacology , Polyphenols/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Alkenes/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Benzofurans/chemistry , COVID-19/drug therapy , Caffeic Acids/chemistry , Cell Survival , HEK293 Cells , Humans , Lactates/chemistry , Molecular Structure , Polyphenols/chemistry , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization
6.
Comput Biol Med ; 126: 104046, 2020 11.
Article in English | MEDLINE | ID: covidwho-837907

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.


Subject(s)
Betacoronavirus/enzymology , Caffeic Acids/chemistry , Coronavirus Infections/drug therapy , Curcumin/chemistry , Cysteine Endopeptidases , Drug Discovery , Lactates/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Pneumonia, Viral/drug therapy , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , COVID-19 , Caffeic Acids/therapeutic use , Coronavirus 3C Proteases , Coronavirus Infections/enzymology , Curcumin/therapeutic use , Cysteine Endopeptidases/chemistry , Humans , Lactates/therapeutic use , Pandemics , Pneumonia, Viral/enzymology , Protease Inhibitors/therapeutic use , SARS-CoV-2 , Thermodynamics , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry
7.
Phytomedicine ; 85: 153310, 2021 May.
Article in English | MEDLINE | ID: covidwho-723883

ABSTRACT

BACKGROUND: SARS-CoV-2, an emerging strain of coronavirus, has affected millions of people from all the continents of world and received worldwide attention. This emerging health crisis calls for the urgent development of specific therapeutics against COVID-19 to potentially reduce the burden of this emerging pandemic. PURPOSE: This study aims to evaluate the anti-viral efficacy of natural bioactive entities against COVID-19 via molecular docking and molecular dynamics simulation. METHODS: A library of 27 caffeic-acid derivatives was screened against 5 proteins of SARS-CoV-2 by using Molegro Virtual Docker 7 to obtain the binding energies and interactions between compounds and SARS-CoV-2 proteins. ADME properties and toxicity profiles were investigated via www.swissadme.ch web tools and Toxtree respectively. Molecular dynamics simulation was performed to determine the stability of the lead-protein interactions. RESULTS: Our obtained results has uncovered khainaoside C, 6-O-Caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as potent modulators of COVID-19 possessing more binding energies than nelfinavir against COVID-19 Mpro, Nsp15, SARS-CoV-2 spike S2 subunit, spike open state and closed state structure respectively. While Calceolarioside B was identified as pan inhibitor, showing strong molecular interactions with all proteins except SARS-CoV-2 spike glycoprotein closed state. The results are supported by 20 ns molecular dynamics simulations of the best complexes. CONCLUSION: This study will hopefully pave a way for development of phytonutrients-based antiviral therapeutic for treatment or prevention of COVID-19 and further studies are recommended to evaluate the antiviral effects of these phytochemicals against SARS-CoV-2 in in vitro and in vivo models.


Subject(s)
Antiviral Agents/pharmacology , Caffeic Acids/pharmacology , Functional Food , SARS-CoV-2/drug effects , Arbutin/analogs & derivatives , Arbutin/pharmacology , Binding Sites , Glucosides/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
8.
Infect Genet Evol ; 84: 104451, 2020 10.
Article in English | MEDLINE | ID: covidwho-630854

ABSTRACT

WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The ever-growing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Nucleocapsid Proteins/chemistry , Viral Envelope Proteins/chemistry , Viral Matrix Proteins/chemistry , Virion/drug effects , Amides , Amino Acid Sequence , Antiviral Agents/chemistry , Betacoronavirus/genetics , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Caffeic Acids/chemistry , Caffeic Acids/pharmacology , Carbamates , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Coumaric Acids/chemistry , Coumaric Acids/pharmacology , Cyclopropanes , Doxycycline/chemistry , Doxycycline/pharmacology , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Nucleocapsid Proteins/antagonists & inhibitors , Nucleocapsid Proteins/genetics , Nucleocapsid Proteins/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quinoxalines/chemistry , Quinoxalines/pharmacology , Rutin/chemistry , Rutin/pharmacology , SARS-CoV-2 , Sequence Alignment , Sequence Homology, Amino Acid , Simeprevir/chemistry , Simeprevir/pharmacology , Sulfonamides , Thermodynamics , Viral Envelope Proteins/antagonists & inhibitors , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism , Viral Matrix Proteins/antagonists & inhibitors , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism , Virion/genetics
9.
J Biomol Struct Dyn ; 39(11): 3842-3854, 2021 07.
Article in English | MEDLINE | ID: covidwho-324383

ABSTRACT

The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, Mpro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 Mpro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Caffeic Acids , Humans , Molecular Docking Simulation , Peptide Hydrolases , Phenylethyl Alcohol/analogs & derivatives , Protease Inhibitors/pharmacology , Withanolides
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