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1.
mBio ; 12(2)2021 03 30.
Article in English | MEDLINE | ID: covidwho-1522913

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 µM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Replication/drug effects , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , Evans Blue/pharmacology , Humans , Molecular Docking Simulation , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sulfones/pharmacology , Surface Plasmon Resonance , Vero Cells
2.
mBio ; 12(2)2021 03 30.
Article in English | MEDLINE | ID: covidwho-1159341

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 µM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Replication/drug effects , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , Evans Blue/pharmacology , Humans , Molecular Docking Simulation , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sulfones/pharmacology , Surface Plasmon Resonance , Vero Cells
3.
Drug Res (Stuttg) ; 71(4): 213-218, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-922287

ABSTRACT

The continued spread of 2019-nCoV has prompted widespread concern around the world. WHO formally named COVID-19 and International Committee on Taxonomy called it Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Due to this viral attack, the whole world is in lockdown. Presently, there is no effective way to control it, except social distancing and hygienic activity. World class scientists and researchers are trying to make vaccine and discover the medicine against the control and cure to this deadly viral disease. Our aim to presenting this article is kick-off deadly viral disease i.e COVID-19 by an easy way with minimum intervention and effort. Different ayurvedic therapeutic agents (Curcuma Longa L, Green tea and Piper nigrum) inhabit entry of virus in host cell, transmission of pathogen and improve the immunity. Curcumin and piperine (1-piperoylpiperidine) interact to each other and form a π-π intermolecular complex which enhance the bioavailability of curcumin by inhibition of glucuronidation of curcumin in liver. Both the molecules curcumin and catechin get bound directly to receptors binding domain of S-protein and ACE-2 receptors of host cell, due to which these molecules inhibit the entry of virus in host cell i. e. animal survives from being infected.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/drug effects , Alkaloids/pharmacology , Animals , Benzodioxoles/pharmacology , COVID-19/virology , Curcumin/pharmacology , Curcumin/therapeutic use , Humans , Piperidines/pharmacology , Polyunsaturated Alkamides/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
4.
J Phys Chem Lett ; 11(19): 8008-8016, 2020 Oct 01.
Article in English | MEDLINE | ID: covidwho-728962

ABSTRACT

The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly spread globally, infecting millions and killing hundreds of thousands of people. Herein, to identify potential antiviral agents, 97 natural amide-like compounds known as alkamides and piperamides were tested against SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), and the human angiotensin-converting enzyme 2 (ACE2) using molecular docking and molecular dynamics simulations. The docking results showed that alkamides and dimeric piperamides from Piper species have a high binding affinity and potential antiviral activity against SARS-CoV-2. The absorption, distribution, metabolism, and excretion (ADME) profile and Lipinski's rule of five showed that dimeric piperamides have druglikeness potential. The molecular dynamics results showed that pipercyclobutanamide B forms a complex with Mpro at a similar level of stability than N3-I. Our overall results indicate that alkamides and piperamides, and specifically pipercyclobutanamide B, should be further studied as compounds with SARS-CoV-2 antiviral properties.


Subject(s)
Amides/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzodioxoles/pharmacology , Benzodioxoles/therapeutic use , Coronavirus Infections/drug therapy , Piper/chemistry , Piperidines/pharmacology , Piperidines/therapeutic use , Pneumonia, Viral/drug therapy , Amides/chemistry , Amides/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacokinetics , Benzodioxoles/pharmacokinetics , Betacoronavirus/drug effects , COVID-19 , Coronavirus 3C Proteases , Cysteine Endopeptidases , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/drug effects , Piperidines/pharmacokinetics , SARS-CoV-2 , Viral Nonstructural Proteins/antagonists & inhibitors
5.
Sci Rep ; 10(1): 13866, 2020 08 17.
Article in English | MEDLINE | ID: covidwho-720849

ABSTRACT

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


Subject(s)
Betacoronavirus/drug effects , Computational Biology/methods , Coronavirus Infections/metabolism , Drug Discovery/methods , Drug Repositioning/methods , Pneumonia, Viral/metabolism , Aminopyridines/pharmacology , Angiotensin-Converting Enzyme 2 , Benzodioxoles/pharmacology , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding/drug effects , Protein Conformation , Protein Domains/drug effects , Protein Interaction Maps/drug effects , SARS-CoV-2 , Simeprevir/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism
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