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1.
Pharmacol Res ; 172: 105820, 2021 10.
Article in English | MEDLINE | ID: covidwho-1531713

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19/drug therapy , Enzyme Inhibitors/chemistry , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antiviral Agents/pharmacology , Binding, Competitive , Biological Products/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Chalcones/pharmacology , Chlorogenic Acid/analogs & derivatives , Chlorogenic Acid/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Ginsenosides/pharmacology , Humans , Interferometry , Mice, Inbred C57BL , Molecular Dynamics Simulation , Phenols/pharmacology , Protein Binding
2.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1518621

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
3.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1480883

ABSTRACT

Viral infections are among the most complex medical problems and have been a major threat to the economy and global health. Several epidemics and pandemics have occurred due to viruses, which has led to a significant increase in mortality and morbidity rates. Natural products have always been an inspiration and source for new drug development because of their various uses. Among all-natural sources, plant sources are the most dominant for the discovery of new therapeutic agents due to their chemical and structural diversity. Despite the traditional use and potential source for drug development, natural products have gained little attention from large pharmaceutical industries. Several plant extracts and isolated compounds have been extensively studied and explored for antiviral properties against different strains of viruses. In this review, we have compiled antiviral plant extracts and natural products isolated from plants reported since 2015.


Subject(s)
Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Development , Plant Extracts/pharmacology , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Drug Discovery , Flavivirus/drug effects , Hepatitis Viruses/drug effects , Humans , Molecular Structure , Orthomyxoviridae/drug effects , Plant Extracts/chemistry , Simplexvirus/drug effects
4.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463775

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
5.
Int J Mol Sci ; 22(19)2021 Oct 02.
Article in English | MEDLINE | ID: covidwho-1463709

ABSTRACT

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Triterpenes/pharmacology , Angiogenesis Inhibitors , Antineoplastic Agents/chemistry , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Triterpenes/chemistry
6.
Int J Biol Macromol ; 191: 1114-1125, 2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1442393

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Biological Products/pharmacokinetics , Biological Products/toxicity , Computer Simulation , Drug Evaluation, Preclinical/methods , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
7.
Bioorg Med Chem ; 46: 116366, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1437407

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, which started in late 2019, drove the scientific community to conduct innovative research to contain the spread of the pandemic and to care for those already affected. Since then, the search for new drugs that are effective against the virus has been strengthened. Featuring a relatively low cost of production under well-defined methods of cultivation, fungi have been providing a diversity of antiviral metabolites with unprecedented chemical structures. In this review, we present viral RNA infections highlighting SARS-CoV-2 morphogenesis and the infectious cycle, the targets of known antiviral drugs, and current developments in this area such as drug repurposing. We also explored the metabolic adaptability of fungi during fermentation to produce metabolites active against RNA viruses, along with their chemical structures, and mechanisms of action. Finally, the state of the art of research on SARS-CoV-2 inhibitors of fungal origin is reported, highlighting the metabolites selected by docking studies.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/drug therapy , Fungi/chemistry , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19/epidemiology , Cell Line , Drug Repositioning , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Pandemics , SARS-CoV-2/physiology
8.
Viruses ; 13(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1383920

ABSTRACT

Viral infections are responsible for several chronic and acute diseases in both humans and animals. Despite the incredible progress in human medicine, several viral diseases, such as acquired immunodeficiency syndrome, respiratory syndromes, and hepatitis, are still associated with high morbidity and mortality rates in humans. Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. In this review, we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Biological Products/chemistry , Biological Products/therapeutic use , DNA Viruses/drug effects , DNA Viruses/physiology , Drug Development , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , RNA Viruses/drug effects , RNA Viruses/physiology , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Virus Diseases/etiology , Virus Diseases/metabolism , Virus Replication/drug effects
9.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-1387198

Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cardiac Glycosides/pharmacology , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/drug effects , Animals , Antiviral Agents/chemistry , Betacoronavirus/pathogenicity , Biological Products/chemistry , Biological Products/pharmacology , Bufanolides/chemistry , Bufanolides/pharmacology , COVID-19 , Cardiac Glycosides/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Digoxin/chemistry , Digoxin/pharmacology , High-Throughput Screening Assays , Host-Pathogen Interactions/genetics , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Vero Cells , Virus Replication/drug effects
10.
Mar Drugs ; 18(10)2020 Sep 26.
Article in English | MEDLINE | ID: covidwho-1389432

ABSTRACT

For a long time, algal chemistry from terrestrial to marine or freshwater bodies, especially chlorophytes, has fascinated numerous investigators to develop new drugs in the nutraceutical and pharmaceutical industries. As such, chlorophytes comprise a diverse structural class of secondary metabolites, having functional groups that are specific to a particular source. All bioactive compounds of chlorophyte are of great interest due to their supplemental/nutritional/pharmacological activities. In this review, a detailed description of the chemical diversity of compounds encompassing alkaloids, terpenes, steroids, fatty acids and glycerides, their subclasses and their structures are discussed. These promising natural products have efficiency in developing new drugs necessary in the treatment of various deadly pathologies (cancer, HIV, SARS-CoV-2, several inflammations, etc.). Marine chlorophyte, therefore, is portrayed as a pivotal treasure in the case of drugs having marine provenience. It is a domain of research expected to probe novel pharmaceutically or nutraceutically important secondary metabolites resulting from marine Chlorophyta. In this regard, our review aims to compile the isolated secondary metabolites having diverse chemical structures from chlorophytes (like Caulerpa ssp., Ulva ssp., Tydemania ssp., Penicillus ssp., Codium ssp., Capsosiphon ssp., Avrainvillea ssp.), their biological properties, applications and possible mode of action.


Subject(s)
Biological Products/pharmacology , Chlorophyta/chemistry , Chlorophyta/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Biological Products/chemistry , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Humans , Neoplasms/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2
11.
Int J Mol Sci ; 22(17)2021 Aug 30.
Article in English | MEDLINE | ID: covidwho-1379978

ABSTRACT

The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (-16.8 Kcal/mol) ranked efficiently with this inhibitor (-16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (-87.60 Kcal/mol) is more energetically favored than N3 (-80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (-87.50 Kcal/mol), Quercetin 3-Rhamnoside (-80.17 Kcal/mol), Rutin (-58.98 Kcal/mol), and Myricitrin (-49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.


Subject(s)
Biological Products/metabolism , SARS-CoV-2/enzymology , Viral Matrix Proteins/metabolism , Binding Sites , Biological Products/chemistry , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Quercetin/analogs & derivatives , Quercetin/chemistry , Quercetin/metabolism , Quercetin/therapeutic use , SARS-CoV-2/isolation & purification , Viral Matrix Proteins/chemistry
12.
Bioorg Med Chem ; 45: 116329, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1372898

ABSTRACT

Agrimonia pilosa (AP), Galla rhois (RG), and their mixture (APRG64) strongly inhibited SARS-CoV-2 by interfering with multiple steps of the viral life cycle including viral entry and replication. Furthermore, among 12 components identified in APRG64, three displayed strong antiviral activity, ursolic acid (1), quercetin (7), and 1,2,3,4,6-penta-O-galloyl-ß-d-glucose (12). Molecular docking analysis showed these components to bind potently to the spike receptor-binding-domain (RBD) of the SARS-CoV-2 and its variant B.1.1.7. Taken together, these findings indicate APRG64 as a potent drug candidate to treat SARS-CoV-2 and its variants.


Subject(s)
Agrimonia/chemistry , Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19/drug therapy , Plant Extracts/chemistry , SARS-CoV-2/drug effects , Amino Acid Sequence , Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Humans , Hydrolyzable Tannins/chemistry , Molecular Docking Simulation , Plant Extracts/pharmacology , Protein Binding , Quercetin/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Triterpenes/chemistry , Virus Internalization/drug effects
13.
Mini Rev Med Chem ; 21(14): 1888-1908, 2021.
Article in English | MEDLINE | ID: covidwho-1323038

ABSTRACT

Virus is a type of noncellular organism, which is simple in structure, small in size and contains only one kind of nucleic acid (RNA or DNA). It must be parasitized in living cells and proliferates by replication. Viruses can infect plants or animals, which leads to many epidemic diseases, such as the current pandemic COVID-19. Viral infectious diseases have brought serious threats to the health of people around the world. Natural products are chemical substances that are usually produced by living organisms and have biological or pharmacological activity. Many of these natural products show antiviral activity. Based on the increasing importance of antiviral research, this paper focuses on the discovery and development of antiviral natural products since 2010.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2 , Animals , Antiviral Agents/chemistry , Biological Products/chemistry , Humans , Plant Viruses/drug effects
14.
Molecules ; 26(12)2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1282543

ABSTRACT

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.


Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Coronavirus 3C Proteases/chemistry , Porifera/chemistry , Porifera/metabolism , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/drug effects , Amino Sugars/chemistry , Amino Sugars/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Biological Products/isolation & purification , Biological Products/pharmacokinetics , COVID-19/drug therapy , Computational Biology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/metabolism
15.
Biomed Res Int ; 2021: 6696012, 2021.
Article in English | MEDLINE | ID: covidwho-1255651

ABSTRACT

A global pandemic has emerged following the appearance of the new severe acute respiratory virus whose official name is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strongly affecting the health sector as well as the world economy. Indeed, following the emergence of this new virus, despite the existence of a few approved and known effective vaccines at the time of writing this original study, a sense of urgency has emerged worldwide to discover new technical tools and new drugs as soon as possible. In this context, many studies and researches are currently underway to develop new tools and therapies against SARS CoV-2 and other viruses, using different approaches. The 3-chymotrypsin (3CL) protease, which is directly involved in the cotranslational and posttranslational modifications of viral polyproteins essential for the existence and replication of the virus in the host, is one of the coronavirus target proteins that has been the subject of these extensive studies. Currently, the majority of these studies are aimed at repurposing already known and clinically approved drugs against this new virus, but this approach is not really successful. Recently, different studies have successfully demonstrated the effectiveness of artificial intelligence-based techniques to understand existing chemical spaces and generate new small molecules that are both effective and efficient. In this framework and for our study, we combined a generative recurrent neural network model with transfer learning methods and active learning-based algorithms to design novel small molecules capable of effectively inhibiting the 3CL protease in human cells. We then analyze these small molecules to find the correct binding site that matches the structure of the 3CL protease of our target virus as well as other analyses performed in this study. Based on these screening results, some molecules have achieved a good binding score close to -18 kcal/mol, which we can consider as good potential candidates for further synthesis and testing against SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Neural Networks, Computer , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Antiviral Agents/classification , Antiviral Agents/pharmacology , Biological Products/classification , Biological Products/pharmacology , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Drug Design , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Protease Inhibitors/classification , Protease Inhibitors/pharmacology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Small Molecule Libraries/classification , Small Molecule Libraries/pharmacology , Substrate Specificity , Thermodynamics
16.
PLoS One ; 16(5): e0251801, 2021.
Article in English | MEDLINE | ID: covidwho-1226905

ABSTRACT

Drug repurposing studies targeting inhibition of RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have exhibited the potential effect of small molecules. In the present work a detailed interaction study between the phytochemicals from Indian medicinal plants and the RdRP of SARS-CoV-2 has been performed. The top four phytochemicals obtained through molecular docking were, swertiapuniside, cordifolide A, sitoindoside IX, and amarogentin belonging to Swertia chirayita, Tinospora cordifolia and Withania somnifera. These ligands bound to the RdRP were further studied using molecular dynamics simulations. The principal component analysis of these systems showed significant conformational changes in the finger and thumb subdomain of the RdRP. Hydrogen bonding, salt-bridge and water mediated interactions supported by MM-GBSA free energy of binding revealed strong binding of cordifolide A and sitoindoside IX to RdRP. The ligand-interacting residues belonged to either of the seven conserved motifs of the RdRP. These residues were polar and charged amino acids, namely, ARG 553, ARG 555, ASP 618, ASP 760, ASP 761, GLU 811, and SER 814. The glycosidic moieties of the phytochemicals were observed to form favourable interactions with these residues. Hence, these phytochemicals may hold the potential to act as RdRP inhibitors owing to their stability in binding to the druggable site.


Subject(s)
COVID-19/drug therapy , Enzyme Inhibitors/pharmacology , Phytochemicals/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Drug Discovery , Enzyme Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals/chemistry , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects
17.
J Mol Model ; 27(6): 160, 2021 May 08.
Article in English | MEDLINE | ID: covidwho-1219702

ABSTRACT

Coronavirus infectious disease 2019 (COVID-19), a viral infection caused by a novel coronavirus (nCoV), continues to emerge as a serious threat to public health. This pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has infected globally with 1,550,000 plus deaths to date, representing a high risk to public health. No effective drug or vaccine is available to curb down this deadly virus. The expedition for searching for a potential drug or vaccine against COVID-19 is of massive potential and favour to the community. This study is focused on finding an effective natural compound that can be processed further into a potential inhibitor to check the activity of SARS-CoV-2 with minimal side effects targeting NSP15 protein, which belongs to the EndoU enzyme family. The natural screening suggested two efficient compounds (PubChem ID: 95372568 and 1776037) with dihydroxyphenyl region of the compound, found to be important in the interaction with the viral protein showing promising activity which may act as a potent lead inhibitory molecule against the virus. In combination with virtual screening, modelling, drug likeliness, molecular docking, and 500 ns cumulative molecular dynamics simulations (100 ns for each complex) along with the decomposition analysis to calculate and confirm the stability and fold, we propose 95372568 and 1776037 as novel compounds of natural origin capable of getting developed into potent lead molecules against SARS-CoV-2 target protein NSP15.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19 , Computational Biology , Endoribonucleases , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/chemistry , Viral Nonstructural Proteins , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , COVID-19/drug therapy , Endoribonucleases/chemistry , Humans , Viral Nonstructural Proteins/chemistry
18.
Molecules ; 26(6)2021 Mar 11.
Article in English | MEDLINE | ID: covidwho-1190434

ABSTRACT

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.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , COVID-19/drug therapy , Receptors, Drug/metabolism , Binding Sites , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Databases, Pharmaceutical , Drug Discovery , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Quantitative Structure-Activity Relationship
19.
Biomolecules ; 11(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1186889

ABSTRACT

The SARS-CoV-2 non-structural protein (nsp) nsp10-nsp16 complex is essential for the 2'-O-methylation of viral mRNA, a crucial step for evading the innate immune system, and it is an essential process in SARS-CoV-2 life cycle. Therefore, detecting molecules that can disrupt the nsp10-nsp16 interaction are prospective antiviral drugs. In this study, we screened the North African Natural Products database (NANPDB) for molecules that can interact with the nsp10 interface and disturb the nsp10-nsp16 complex formation. Following rigorous screening and validation steps, in addition to toxic side effects, drug interactions and a risk /benefit assessment, we identified four compounds (genkwanin-6-C-beta-glucopyranoside, paraliane diterpene, 4,5-di-p-trans-coumaroylquinic acid and citrinamide A) that showed the best binding affinity and most favourable interaction with nsp10 interface residues. To understand the conformational stability and dynamic features of nsp10 bound to the four selected compounds, we subjected each complex to 200 ns molecular dynamics simulations. We then calculated the free binding energies of compounds interacting with nsp10 structure using the molecular mechanics-generalised Born surface area (MMGBSA). Of the four compounds, genkwanin-6-C-beta-glucopyranoside demonstrated the most stable complex with nsp10, in addition to a tighter binding affinity of -37.4 ± 1.3 Kcal/mol. This potential to disrupt the nsp10-nsp16 interface interaction and inhibit it now sets the path for functional studies.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/metabolism , Antiviral Agents/chemistry , Biological Products/chemistry , Drug Discovery , Humans , Methyltransferases , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Interaction Maps/drug effects , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Regulatory and Accessory Proteins/antagonists & inhibitors
20.
Molecules ; 26(6)2021 Mar 21.
Article in English | MEDLINE | ID: covidwho-1143540

ABSTRACT

Since the emergence of severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) first reported in Wuhan, China in December 2019, COVID-19 has spread to all the continents at an unprecedented pace. This pandemic has caused not only hundreds of thousands of mortalities but also a huge economic setback throughout the world. Therefore, the scientific communities around the world have focused on finding antiviral therapeutic agents to either fight or halt the spread of SARS-CoV-2. Since certain medicinal plants and herbal formulae have proved to be effective in treatment of similar viral infections such as those caused by SARS and Ebola, scientists have paid more attention to natural products for effective treatment of this devastating pandemic. This review summarizes studies and ethnobotanical information on plants and their constituents used for treatment of infections caused by viruses related to the coronavirus family. Herein, we provide a critical analysis of previous reports and how to exploit published data for the discovery of novel therapeutic leads to fight against COVID-19.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Plants, Medicinal/chemistry , Severe Acute Respiratory Syndrome/drug therapy , Animals , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , Humans , SARS Virus/drug effects , SARS Virus/metabolism , Secondary Metabolism
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