Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 23
Filter
2.
J Mol Model ; 27(11): 341, 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1499466

ABSTRACT

From the beginning of pandemic, more than 240 million people have been infected with a death rate higher than 2%. Indeed, the current exit strategy involving the spreading of vaccines must be combined with progress in effective treatment development. This scenario is sadly supported by the vaccine's immune activation time and the inequalities in the global immunization schedule. Bringing the crises under control means providing the world population with accessible and impactful new therapeutics. We screened a natural product library that contains a unique collection of 2370 natural products into the binding site of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). According to the docking score and to the interaction at the active site, three phenylethanoid glycosides (forsythiaside A, isoacteoside, and verbascoside) were selected. In order to provide better insight into the atomistic interaction and test the impact of the three selected compounds at the binding site, we resorted to a half microsecond-long molecular dynamics simulation. As a result, we are showing that forsythiaside A is the most stable molecule and it is likely to possess the highest inhibitory effect against SARS-CoV-2 Mpro. Phenylethanoid glycosides also have been reported to have both protease and kinase activity. This kinase inhibitory activity is very beneficial in fighting viruses inside the body as kinases are required for viral entry, metabolism, and/or reproduction. The dual activity (kinase/protease) of phenylethanoid glycosides makes them very promising anit-COVID-19 agents.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Glycosides/pharmacology , Antiviral Agents/chemistry , Binding Sites , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemistry , Drug Evaluation, Preclinical , Glucosides/chemistry , Glucosides/metabolism , Glucosides/pharmacology , Glycosides/chemistry , Glycosides/metabolism , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenols/chemistry , Phenols/metabolism , Phenols/pharmacology
3.
Sci Rep ; 11(1): 17748, 2021 09 07.
Article in English | MEDLINE | ID: covidwho-1412634

ABSTRACT

Based on WHO reports the new SARS-CoV-2 coronavirus is currently widespread all over the world. So far > 162 million cases have been confirmed, including > 3 million deaths. Because of the pandemic still spreading across the globe the accomplishment of computational methods to find new potential mechanisms of virus inhibitions is necessary. According to the fact that C60 fullerene (a sphere-shaped molecule consisting of carbon) has shown inhibitory activity against various protein targets, here the analysis of the potential binding mechanism between SARS-CoV-2 proteins 3CLpro and RdRp with C60 fullerene was done; it has resulted in one and two possible binding mechanisms, respectively. In the case of 3CLpro, C60 fullerene interacts in the catalytic binding pocket. And for RdRp in the first model C60 fullerene blocks RNA synthesis pore and in the second one it prevents binding with Nsp8 co-factor (without this complex formation, RdRp can't perform its initial functions). Then the molecular dynamics simulation confirmed the stability of created complexes. The obtained results might be a basis for other computational studies of 3CLPro and RdRp potential inhibition ways as well as the potential usage of C60 fullerene in the fight against COVID-19 disease.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Fullerenes/pharmacology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/ultrastructure , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Coronavirus Protease Inhibitors/therapeutic use , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/ultrastructure , Crystallography, X-Ray , Fullerenes/chemistry , Fullerenes/therapeutic use , Humans , Molecular Dynamics Simulation , Nucleic Acid Synthesis Inhibitors/chemistry , Nucleic Acid Synthesis Inhibitors/pharmacology , Nucleic Acid Synthesis Inhibitors/therapeutic use , Pandemics/prevention & control , RNA, Viral/biosynthesis , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , SARS-CoV-2/ultrastructure
4.
Sci Rep ; 11(1): 17748, 2021 09 07.
Article in English | MEDLINE | ID: covidwho-1397901

ABSTRACT

Based on WHO reports the new SARS-CoV-2 coronavirus is currently widespread all over the world. So far > 162 million cases have been confirmed, including > 3 million deaths. Because of the pandemic still spreading across the globe the accomplishment of computational methods to find new potential mechanisms of virus inhibitions is necessary. According to the fact that C60 fullerene (a sphere-shaped molecule consisting of carbon) has shown inhibitory activity against various protein targets, here the analysis of the potential binding mechanism between SARS-CoV-2 proteins 3CLpro and RdRp with C60 fullerene was done; it has resulted in one and two possible binding mechanisms, respectively. In the case of 3CLpro, C60 fullerene interacts in the catalytic binding pocket. And for RdRp in the first model C60 fullerene blocks RNA synthesis pore and in the second one it prevents binding with Nsp8 co-factor (without this complex formation, RdRp can't perform its initial functions). Then the molecular dynamics simulation confirmed the stability of created complexes. The obtained results might be a basis for other computational studies of 3CLPro and RdRp potential inhibition ways as well as the potential usage of C60 fullerene in the fight against COVID-19 disease.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Fullerenes/pharmacology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/ultrastructure , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Coronavirus Protease Inhibitors/therapeutic use , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/ultrastructure , Crystallography, X-Ray , Fullerenes/chemistry , Fullerenes/therapeutic use , Humans , Molecular Dynamics Simulation , Nucleic Acid Synthesis Inhibitors/chemistry , Nucleic Acid Synthesis Inhibitors/pharmacology , Nucleic Acid Synthesis Inhibitors/therapeutic use , Pandemics/prevention & control , RNA, Viral/biosynthesis , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , SARS-CoV-2/ultrastructure
5.
Nat Commun ; 12(1): 668, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1387328

ABSTRACT

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 µM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.


Subject(s)
COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Viral Proteases/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Humans , Indoles/pharmacology , Pyridines/pharmacology , Vero Cells , Viral Proteases/metabolism
6.
Molecules ; 26(17)2021 Aug 28.
Article in English | MEDLINE | ID: covidwho-1374472

ABSTRACT

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2'-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3ß-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of -87.91, -78.11, and -68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Ginger/chemistry , Plant Extracts/pharmacology , Coronavirus 3C Proteases/metabolism , Coronavirus 3C Proteases/ultrastructure , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/isolation & purification , Coronavirus Protease Inhibitors/therapeutic use , Crystallography, X-Ray , Enzyme Assays , Gas Chromatography-Mass Spectrometry , Humans , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Pyrrolidines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Structure-Activity Relationship , Sulfonic Acids/pharmacology
7.
Molecules ; 26(17)2021 Aug 24.
Article in English | MEDLINE | ID: covidwho-1374471

ABSTRACT

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (-16.8 ± 0.02 kcal/mol, -12.3 ± 0.03 kcal/mol and -13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Bacterial Proteins/pharmacology , COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , Antiviral Agents/therapeutic use , Bacterial Proteins/therapeutic use , Bacterial Proteins/ultrastructure , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Coronavirus 3C Proteases/ultrastructure , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolism , Coronavirus Papain-Like Proteases/ultrastructure , Coronavirus Protease Inhibitors/therapeutic use , Coronavirus Protease Inhibitors/ultrastructure , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Interaction Mapping , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/ultrastructure , X-Ray Diffraction
8.
Int J Mol Sci ; 22(17)2021 Aug 24.
Article in English | MEDLINE | ID: covidwho-1374423

ABSTRACT

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Lactams/pharmacology , Leucine/pharmacology , Nitriles/pharmacology , Proline/pharmacology , Antiviral Agents/therapeutic use , Catalytic Domain/drug effects , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/therapeutic use , Humans , Lactams/therapeutic use , Leucine/therapeutic use , Lopinavir/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
9.
Int J Biol Macromol ; 188: 137-146, 2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1345340

ABSTRACT

COVID-19 is a disease caused by SARS-CoV-2, which has led to more than 4 million deaths worldwide. As a result, there is a worldwide effort to develop specific drugs for targeting COVID-19. Papain-like protease (PLpro) is an attractive drug target because it has multiple essential functions involved in processing viral proteins, including viral genome replication and removal of post-translational ubiquitination modifications. Here, we established two assays for screening PLpro inhibitors according to protease and anti-ISGylation activities, respectively. Application of the two screening techniques to the library of clinically approved drugs led to the discovery of tanshinone IIA sulfonate sodium and chloroxine with their IC50 values of lower than 10 µM. These two compounds were found to directly interact with PLpro and their molecular mechanisms of binding were illustrated by docking and molecular dynamics simulations. The results highlight the usefulness of the two developed screening techniques for locating PLpro inhibitors.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Drug Repositioning , SARS-CoV-2/enzymology , Antiviral Agents/chemistry , Binding Sites , Chloroquinolinols/chemistry , Chloroquinolinols/pharmacology , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/isolation & purification , Coronavirus Protease Inhibitors/chemistry , High-Throughput Screening Assays/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , SARS-CoV-2/drug effects
10.
Int J Mol Sci ; 22(14)2021 Jul 19.
Article in English | MEDLINE | ID: covidwho-1323269

ABSTRACT

In the last year, the COVID-19 pandemic has highly affected the lifestyle of the world population, encouraging the scientific community towards a great effort on studying the infection molecular mechanisms. Several vaccine formulations are nowadays available and helping to reach immunity. Nevertheless, there is a growing interest towards the development of novel anti-covid drugs. In this scenario, the main protease (Mpro) represents an appealing target, being the enzyme responsible for the cleavage of polypeptides during the viral genome transcription. With the aim of sharing new insights for the design of novel Mpro inhibitors, our research group developed a machine learning approach using the support vector machine (SVM) classification. Starting from a dataset of two million commercially available compounds, the model was able to classify two hundred novel chemo-types as potentially active against the viral protease. The compounds labelled as actives by SVM were next evaluated through consensus docking studies on two PDB structures and their binding mode was compared to well-known protease inhibitors. The best five compounds selected by consensus docking were then submitted to molecular dynamics to deepen binding interactions stability. Of note, the compounds selected via SVM retrieved all the most important interactions known in the literature.


Subject(s)
COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , Drug Evaluation, Preclinical/methods , SARS-CoV-2/drug effects , Support Vector Machine , Antiviral Agents/pharmacology , COVID-19/virology , Coronavirus Protease Inhibitors/metabolism , Databases, Pharmaceutical , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , SARS-CoV-2/enzymology , Small Molecule Libraries , Supervised Machine Learning , Viral Nonstructural Proteins/metabolism , Viral Proteases/metabolism
11.
Mar Drugs ; 19(7)2021 Jul 13.
Article in English | MEDLINE | ID: covidwho-1314693

ABSTRACT

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.


Subject(s)
Anthozoa/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Diterpenes/pharmacology , SARS-CoV-2/drug effects , Animals , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/isolation & purification , Diterpenes/chemistry , Diterpenes/isolation & purification , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , SARS-CoV-2/enzymology , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
12.
Fitoterapia ; 152: 104909, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1203052

ABSTRACT

3-Chymotrypsin-like protease (3CLpro) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CLpro inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CLpro inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CLpro, Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CLpro inhibition activity (IC50 = 6.68 µg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CLpro inhibition activities (IC50 < 10 µM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CLpro inhibition activities, with IC50 values of less than 2 µM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CLprovia a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CLpro inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CLpro.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 , Coronavirus Protease Inhibitors/pharmacology , Ginkgo biloba/chemistry , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Antiviral Agents/therapeutic use , Biflavonoids/pharmacology , Biflavonoids/therapeutic use , COVID-19/drug therapy , Coronavirus Protease Inhibitors/therapeutic use , Flavones/pharmacology , Flavones/therapeutic use , Humans , Molecular Structure , Phytotherapy , Plant Extracts/therapeutic use , Plant Leaves/chemistry , SARS-CoV-2/enzymology , Salicylates/pharmacology , Salicylates/therapeutic use
13.
Biochem Biophys Res Commun ; 538: 72-79, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1139451

ABSTRACT

SARS-CoV-2 papain-like protease is considered as an important potential target for anti-SARS-CoV-2 drug discovery due to its crucial roles in viral spread and innate immunity. Here, we have utilized an in silico molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 papain-like protease, by screening 21 antiviral, antifungal and anticancer compounds. Among them, Neobavaisoflavone has the highest binding energy for SARS-CoV-2 papain-like protease. These molecules could bind near the SARS-CoV-2 papain-like protease crucial catalytic triad, ubiquitination and ISGylation residues: Trp106, Asn109, Cys111, Met208, Lys232, Pro247, Tyr268, Gln269, His272, Asp286 and Thr301. Because blocking the papain-like protease is an important strategy in fighting against viruses, these compounds might be promising candidates for therapeutic intervention against COVID-19.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , Coronavirus Protease Inhibitors/chemistry , Cysteine Proteinase Inhibitors/chemistry , Drug Discovery/methods , Isoflavones/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Humans , Isoflavones/pharmacology , Ligands , Molecular Docking Simulation , Protein Binding
14.
Biochem Biophys Res Commun ; 538: 63-71, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1125596

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented global health crisis. It is particularly urgent to develop clinically effective therapies to contain the pandemic. The main protease (Mpro) and the RNA-dependent RNA polymerase (RdRP), which are responsible for the viral polyprotein proteolytic process and viral genome replication and transcription, respectively, are two attractive drug targets for SARS-CoV-2. This review summarizes up-to-date progress in the structural and pharmacological aspects of those two key targets above. Different classes of inhibitors individually targeting Mpro and RdRP are discussed, which could promote drug development to treat SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus Protease Inhibitors/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Enzyme Inhibitors/chemistry , SARS-CoV-2/enzymology , Antiviral Agents/pharmacology , Coronavirus Protease Inhibitors/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Protein Conformation , SARS-CoV-2/drug effects
15.
Chem Soc Rev ; 50(6): 3647-3655, 2021 Mar 21.
Article in English | MEDLINE | ID: covidwho-1057718

ABSTRACT

Clinically approved antiviral drugs are currently available for only 10 of the more than 220 viruses known to infect humans. The SARS-CoV-2 outbreak has exposed the critical need for compounds that can be rapidly mobilised for the treatment of re-emerging or emerging viral diseases, while vaccine development is underway. We review the current status of antiviral therapies focusing on RNA viruses, highlighting strategies for antiviral drug discovery and discuss the challenges, solutions and options to accelerate drug discovery efforts.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery/methods , Molecular Targeted Therapy/methods , Pandemics/prevention & control , RNA, Viral/antagonists & inhibitors , Antiviral Agents/chemistry , Biological Products/chemistry , Biological Products/pharmacology , COVID-19/prevention & control , COVID-19/virology , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Nucleic Acid Synthesis Inhibitors/chemistry , Nucleic Acid Synthesis Inhibitors/pharmacology , RNA, Viral/chemistry , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology
16.
J Infect Public Health ; 13(12): 1856-1861, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1023653

ABSTRACT

BACKGROUND: Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2. METHODS: The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated. RESULTS: Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties. CONCLUSION: This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Drug Repositioning , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Indinavir/pharmacology , Molecular Docking Simulation , Nitriles/pharmacology , Oxazines/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Pyridones/pharmacology , Pyrimidines/pharmacology , Pyrones/pharmacology , Raltegravir Potassium/pharmacology , SARS-CoV-2/enzymology , Sulfonamides/pharmacology
17.
Comput Biol Chem ; 89: 107408, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-898662

ABSTRACT

Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 pandemic is ongoing, with no proven safe and effective vaccine to date. Further, effective therapeutic agents for COVID-19 are limited, and as a result, the identification of potential small molecule antiviral drugs is of particular importance. A critical antiviral target is the SARS-CoV-2 main protease (Mpro), and our aim was to identify lead compounds with potential inhibitory effects. We performed an initial molecular docking screen of 300 small molecules, which included phenolic compounds and fatty acids from our OliveNet™ library (224), and an additional group of curated pharmacological and dietary compounds. The prototypical α-ketoamide 13b inhibitor was used as a control to guide selection of the top 30 compounds with respect to binding affinity to the Mpro active site. Further studies and analyses including blind docking were performed to identify hypericin, cyanidin-3-O-glucoside and SRT2104 as potential leads. Molecular dynamics simulations demonstrated that hypericin (ΔG = -18.6 and -19.3 kcal/mol), cyanidin-3-O-glucoside (ΔG = -50.8 and -42.1 kcal/mol), and SRT2104 (ΔG = -8.7 and -20.6 kcal/mol), formed stable interactions with the Mpro active site. An enzyme-linked immunosorbent assay indicated that, albeit, not as potent as the covalent positive control (GC376), our leads inhibited the Mpro with activity in the micromolar range, and an order of effectiveness of hypericin and cyanidin-3-O-glucoside > SRT2104 > SRT1720. Overall, our findings, and those highlighted by others indicate that hypericin and cyanidin-3-O-glucoside are suitable candidates for progress to in vitro and in vivo antiviral studies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Antiviral Agents/chemistry , Coronavirus Protease Inhibitors/chemistry , Fatty Acids/chemistry , Fatty Acids/pharmacology , Humans , Ligands , Microbial Sensitivity Tests , Models, Molecular , Phenols/chemistry , Phenols/pharmacology , SARS-CoV-2/metabolism , Small Molecule Libraries/chemistry
18.
ACS Comb Sci ; 22(12): 826-832, 2020 12 14.
Article in English | MEDLINE | ID: covidwho-894367

ABSTRACT

The current COVID-19 pandemic caused by a novel coronavirus SARS-CoV-2 urgently calls for a working therapeutic. Here, we report a computation-based workflow for efficiently selecting a subset of FDA-approved drugs that can potentially bind to the SARS-CoV-2 main protease MPRO. The workflow started with docking (using Autodock Vina) each of 1615 FDA-approved drugs to the MPRO active site. This step selected 62 candidates with docking energies lower than -8.5 kcal/mol. Then, the 62 docked protein-drug complexes were subjected to 100 ns of molecular dynamics (MD) simulations in a molecular mechanics (MM) force field (CHARMM36). This step reduced the candidate pool to 26, based on the root-mean-square-deviations (RMSDs) of the drug molecules in the trajectories. Finally, we modeled the 26 drug molecules by a pseudoquantum mechanical (ANI) force field and ran 5 ns hybrid ANI/MM MD simulations of the 26 protein-drug complexes. ANI was trained by neural network models on quantum mechanical density functional theory (wB97X/6-31G(d)) data points. An RMSD cutoff winnowed down the pool to 12, and free energy analysis (MM/PBSA) produced the final selection of 9 drugs: dihydroergotamine, midostaurin, ziprasidone, etoposide, apixaban, fluorescein, tadalafil, rolapitant, and palbociclib. Of these, three are found to be active in literature reports of experimental studies. To provide physical insight into their mechanism of action, the interactions of the drug molecules with the protein are presented as 2D-interaction maps. These findings and mappings of drug-protein interactions may be potentially used to guide rational drug discovery against COVID-19.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/chemistry , Coronavirus Protease Inhibitors/chemistry , Drug Discovery/methods , Drug Repositioning , Neural Networks, Computer , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Molecular Dynamics Simulation , Protein Binding , Workflow
19.
Hum Vaccin Immunother ; 17(4): 1113-1121, 2021 04 03.
Article in English | MEDLINE | ID: covidwho-872899

ABSTRACT

A novel coronavirus (2019-nCov) emerged in China, at the end of December 2019 which posed an International Public Health Emergency, and later declared as a global pandemic by the World Health Organization (WHO). The International Committee on Taxonomy of Viruses (ICTV) named it SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), while the disease was named COVID-19 (Coronavirus Disease- 2019). Many questions related to the exact mode of transmission, animal origins, and antiviral therapeutics are not clear yet. Nevertheless, it is required to urgently launch a new protocol to evaluate the side effects of unapproved vaccines and antiviral therapeutics to accelerate the clinical application of new drugs. In this review, we highlight the most salient characteristics and recent findings of COVID-19 disease, molecular virology, interspecies mechanisms, and health consequences related to this disease.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Vaccines/immunology , COVID-19/pathology , COVID-19/transmission , Coronavirus Protease Inhibitors/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antiviral Agents/adverse effects , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Chiroptera/virology , Humans , Lopinavir/pharmacology , Ritonavir/pharmacology , SARS-CoV-2/drug effects , Virus Attachment , Virus Internalization
20.
Curr Drug Discov Technol ; 18(5): e17092020186048, 2021.
Article in English | MEDLINE | ID: covidwho-789063

ABSTRACT

BACKGROUND: The recent outbreak of Coronavirus SARS-CoV-2 (Covid-19), which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. METHODS: Compounds previously characterized by Melissa officinalis were queried against the main protease of coronavirus SARS-CoV-2 using a computational approach. RESULTS: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of the QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_ 28 (R2 = 0.8548 and Q2=0.6474, which was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. CONCLUSION: Salvanolic acid A can be further evaluated as a potential Mpro inhibitor.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Melissa/chemistry , SARS-CoV-2 , Antiviral Agents/pharmacology , Drug Discovery , Humans , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Plants, Medicinal , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...