Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
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
2.
Molecules ; 26(21)2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1488678

ABSTRACT

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).


Subject(s)
Coronavirus Papain-Like Proteases/metabolism , SARS-CoV-2/drug effects , Virus Replication/drug effects , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Computer Simulation , Coronavirus Papain-Like Proteases/drug effects , Drug Evaluation, Preclinical/methods , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Papain/metabolism , Peptide Hydrolases/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
3.
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
4.
Journal of Chemistry ; : 1-14, 2021.
Article in English | Academic Search Complete | ID: covidwho-1350067

ABSTRACT

Chromatographic fractionation of the methanolic extract of Asteriscus hierochunticus whole plant led to the identification of a new humulene glucoside (1). The chemical structure of the isolated compound was elucidated by IR, 1D, 2D NMR, and HRESIMS data analysis to be (-)-(2Z,6E,9E)8α-hydroxy-2,6,9-humulatrien-1(12)-olide. In this study, we report the in silico binding affinities of 1 against four different SARS-CoV-2 proteins (COVID-19 main protease (PDB ID: 6lu7), nonstructural protein (PDB ID: 6W4H), RNA-dependent RNA polymerase (PDB ID: 7BV2), and SARS-CoV-2 helicase (PDB ID: 5RMM)). The isolated compound showed excellent binding affinity values (ΔG) of −21.65, −20.05, −28.93, and −21.73 kcal/mol, respectively, against the target proteins compared to the cocrystallized ligands that exhibited ΔG values of −23.75, −17.65, −23.57, and −15.30 kcal/mol, respectively. Further in silico investigations of the isolated compound (1) for its ADMET and toxicity profiles revealed excellent drug likeliness. On the other hand, the results obtained from in vitro antitrypanosomal, antileishmanial, and antimalarial activities of (1) were not promising. [ABSTRACT FROM AUTHOR] Copyright of Journal of Chemistry is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

5.
Journal of Chemistry ; : 1-8, 2021.
Article in English | Academic Search Complete | ID: covidwho-1247433

ABSTRACT

The emergence of the COVID-19 pandemic declared the huge need of humanity for new and effective antiviral drugs. The reported antimicrobial activities of Artemisia sublessingiana encouraged us to investigate the ethanol extract of its aerial parts which led to the isolation of six flavonoids and a sesquiterpenoid. The structures of the isolated compounds were elucidated by EI-MS, 1D, and 2D NMR spectroscopic methods to be (1) eupatilin, (2) 3′,4′-dimethoxyluteolin, (3) 5,7,3′-trihydroxy-6,4′,5′-trimethoxyflavone, (4) hispidulin, (5) apigenin, (6) velutin, and (7) sesquiterpene lactone 8α,14-dihydroxy-11,13-dihydromelampolide. The isolated compounds were in silico examined against the COVID-19 main protease (Mpro) enzyme. Compounds 1–6 exhibited promising binding modes showing free energies ranging from −6.39 to −6.81 (kcal/mol). The best binding energy was for compound 2. The obtained results give hope of finding a treatment for the COVID-19 pandemic. [ABSTRACT FROM AUTHOR] Copyright of Journal of Chemistry is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

6.
Front Chem ; 9: 661230, 2021.
Article in English | MEDLINE | ID: covidwho-1238863

ABSTRACT

The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.

7.
Molecules ; 26(9)2021 May 10.
Article in English | MEDLINE | ID: covidwho-1224075

ABSTRACT

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the "COVID-19" disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from -24.02 to -39.33 kcal mol-1, compared to the co-crystallized ligand (-21.39 kcal mol-1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from -32.19 to -50.79 kcal mol-1, comparing to the co-crystallized ligand (binding energy = -62.84 kcal mol-1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases/chemistry , Drug Delivery Systems , Isoflavones/chemistry , Molecular Docking Simulation , Angiotensin-Converting Enzyme 2/metabolism , Coronavirus 3C Proteases/metabolism , Humans , Isoflavones/therapeutic use
8.
Biomolecules ; 11(3)2021 03 19.
Article in English | MEDLINE | ID: covidwho-1148287

ABSTRACT

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.


Subject(s)
Alkaloids/chemistry , Antiviral Agents/chemistry , Coronavirus Nucleocapsid Proteins/chemistry , Porifera/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/toxicity , Blood-Brain Barrier , Crystallography, X-Ray , Ligands , Membrane Glycoproteins/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Phosphoproteins/chemistry , Protease Inhibitors/chemistry , Rats , Software , Viral Proteases/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...