scholarly journals SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1409
Author(s):  
Anna Maria Sardanelli ◽  
Camilla Isgrò ◽  
Luigi Leonardo Palese
Keyword(s):  
Active Site ◽  
Therapeutic Strategy ◽  
Silybum Marianum ◽  
Antiviral Therapies ◽  
Global Pandemic ◽  
Main Protease ◽  
Toxicological Profile ◽  
Starting Point ◽  
Antiviral Activities

In late 2019, a global pandemic occurred. The causative agent was identified as a member of the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we present an analysis on the substances identified in the human metabolome capable of binding the active site of the SARS-CoV-2 main protease (Mpro). The substances present in the human metabolome have both endogenous and exogenous origins. The aim of this research was to find molecules whose biochemical and toxicological profile was known that could be the starting point for the development of antiviral therapies. Our analysis revealed numerous metabolites—including xenobiotics—that bind this protease, which are essential to the lifecycle of the virus. Among these substances, silybin, a flavolignan compound and the main active component of silymarin, is particularly noteworthy. Silymarin is a standardized extract of milk thistle, Silybum marianum, and has been shown to exhibit antioxidant, hepatoprotective, antineoplastic, and antiviral activities. Our results—obtained in silico and in vitro—prove that silybin and silymarin, respectively, are able to inhibit Mpro, representing a possible food-derived natural compound that is useful as a therapeutic strategy against COVID-19.

scholarly journals Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

2020 ◽  
Author(s):  
Hongbo Liu ◽  
Fei Ye ◽  
Qi Sun ◽  
Hao Liang ◽  
Chunmei Li ◽  
...  
Keyword(s):  
Ethanol Extract ◽  
Vero Cells ◽  
Scutellaria Baicalensis ◽  
Scutellariae Radix ◽  
Global Pandemic ◽  
Main Protease ◽  
Antiviral Activities ◽  
Viral Polyprotein ◽  
Effective Drugs

AbstractCOVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts of S. baicalensis have exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredient compounds. We found that the ethanol extract of S. baicalensis inhibits SARS-CoV-2 3CLpro activity in vitro and the replication of SARS-CoV-2 in Vero cells with an EC50 of 0.74 μg/ml. Among the major components of S. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLpro activity with an IC50 of 0.39 μM. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. Our study demonstrates that the extract of S. baicalensis has effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLpro inhibitors.

scholarly journals Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 106
Author(s):  
Camilla Isgrò ◽  
Anna Maria Sardanelli ◽  
Luigi Leonardo Palese
Keyword(s):  
Therapeutic Strategy ◽  
Ethacrynic Acid ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
High Morbidity ◽  
Global Pandemic ◽  
Main Protease ◽  
Starting Point ◽  
Effective Therapeutic Strategy

In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.

In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

2021 ◽  
Vol 18 ◽  
Author(s):  
Jainey James ◽  
Divya Jyothi ◽  
Sneh Priya
Keyword(s):  
Antiviral Activity ◽  
Molecular Interactions ◽  
In Silico ◽  
Antiviral Treatment ◽  
In Vivo Studies ◽  
Main Protease ◽  
Hypothesis Model ◽  
Antiviral Activities ◽  
Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

scholarly journals Allosteric inhibition of the SARS-CoV-2 main protease – insights from mass spectrometry-based assays

2020 ◽  
Author(s):  
Tarick J. El-Baba ◽  
Corinne A. Lutomski ◽  
Anastassia L. Kantsadi ◽  
Tika R. Malla ◽  
Tobias John ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Native Mass Spectrometry ◽  
Turnover Rates ◽  
Kinetic Assay ◽  
Antiviral Therapies ◽  
Enzyme Substrate ◽  
Main Protease ◽  
Starting Point ◽  
Catalytically Active ◽  
Substrate Processing

AbstractFollowing translation of the SARS-CoV-2 RNA genome into two viral polypeptides, the main protease Mpro cleaves at eleven sites to release non-structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus-2019 disease (COVID-19). Here, we have used native mass spectrometry (MS) to characterize the functional unit of Mpro. Analysis of the monomer-dimer equilibria reveals a dissociation constant of Kd = 0.14 ± 0.03 μM, revealing MPro has a strong preference to dimerize in solution. Developing an MS-based kinetic assay we then characterized substrate turnover rates by following temporal changes in the enzyme-substrate complexes, which are effectively “flash-frozen” as they transition from solution to the gas phase. We screened small molecules, that bind distant from the active site, for their ability to modulate activity. These compounds, including one proposed to disrupt the catalytically active dimer, slow the rate of substrate processing by ~35%. This information was readily obtained and, together with analysis of the x-ray crystal structures of these enzyme-small molecule complexes, provides a starting point for the development of more potent molecules that allosterically regulate MPro activity.

scholarly journals High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3193 ◽  
Author(s):  
Olujide O. Olubiyi ◽  
Maryam Olagunju ◽  
Monika Keutmann ◽  
Jennifer Loschwitz ◽  
Birgit Strodel
Keyword(s):  
Natural Products ◽  
Kinase Inhibitors ◽  
Amino Acid Residues ◽  
Enzyme Dynamics ◽  
Hydrogen Bond Formation ◽  
Protease Enzyme ◽  
Main Protease ◽  
Starting Point ◽  
Approved Drugs

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

scholarly journals Natural Compounds from Djiboutian Medicinal Plants as Inhibitors of COVID-19 by in Silico Investigations

2020 ◽  
Author(s):  
abdirahman elmi ◽  
S. al jawad sayem ◽  
Mohamed Ahmed ◽  
fatouma mohamed
Keyword(s):  
Medicinal Plants ◽  
Natural Compounds ◽  
Binding Energies ◽  
Receptor Binding Domain ◽  
Global Pandemic ◽  
Main Protease ◽  
Target Sites ◽  
Better Than

The new coronavirus type SARS-Cov 2 (severe acute respiratory syndrome), which appeared in autumn 2019 in China, became a global pandemic in a few months. In this work, we looked for the potential anti SARS-Cov 2 of the compounds isolated from three Djiboutian medicinal plants namely Acacia seyal, Cymbopogon commutatus, and Indigofera caerulea. For this we carried out a docking with nine biomolecules, β-Sitosterol , Quercetin, Catechin, Lupeol, Rutin, Kaempferol, Gallic acid, Piperitone and Limonene on three target sites which are SARS-CoV-2 main protease (Mp), SARS-CoV-2 receptor binding domain (RBD) and human furin protease. These targets are chosen because of their role in the process of penetration of the virus into human cells and its multiplication. The phenolic compounds have a very good afinity on these three target sites with binding energies of up to -9.098 kcal/mol for rutin on SARS-CoV-2 Mp, much better than the two reference drugs hydroxychloroquine (-5.816 kcal / mol) and remdesivir (-7.194 kcal/mol). These natural compounds do not present toxicities and can be used pending In vitro and In vivo evaluations.

scholarly journals An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19

2021 ◽  
Author(s):  
Dafydd R Owen ◽  
Charlotte M N Allerton ◽  
Annaliesa S Anderson ◽  
Lisa Aschenbrenner ◽  
Melissa Avery ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasma Concentrations ◽  
Healthy Human ◽  
Clinical Trial Registration ◽  
Global Pandemic ◽  
Main Protease ◽  
Orally Bioavailable ◽  
Human Participants

The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity, and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency, in a phase I clinical trial in healthy human participants. Clinical Trial Registration ID #: NCT04756531

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

scholarly journals Discovery of Potent Covid-19 Main Protease Inhibitors Using Machine Learning Based Virtual Screening Strategy

2020 ◽  
Author(s):  
Muthu Kumar T ◽  
Rohini K ◽  
Nivya James ◽  
Shanthi V ◽  
Ramanathan Karuppasamy
Keyword(s):  
Machine Learning ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Screening Strategy ◽  
Antiviral Therapies ◽  
Drug Molecules ◽  
Main Protease ◽  
Antiviral Activities ◽  
Imminent Threat ◽  
Potential Inhibitors

<p>The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the great role of main protease of Covid-19 for virus replication, we performed drug repurposing study using recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR respectively were developed using available small molecule inhibitors and utilized in the screening of DrugBank repository. Further, hierarchical docking protocol was implemented with the support of Glide algorithm. The resultant compounds were then examined for its binding free energy against main protease of Covid-19 by means of Prime-MM/GBSA algorithm. Most importantly, the resultant compounds antiviral activities were further predicted by machine learning-based model generated by AutoQSAR algorithm. Finally, the hit molecules were examined for its drug likeness and its toxicity parameters through QikProp algorithm. Overall, the present analysis yielded four potential inhibitors (DB07800, DB08573, DB03744 and DB02986) that are predicted to bind with main protease of Covid-19 better than currently used drug molecules such as N3 (co-crystallized native ligand), Lopinavir and Ritonavir. </p>

scholarly journals NATURAL COMPOUNDS FROM DJIBOUTIAN MEDICINAL PLANTS AS INHIBITORS OF COVID-19 BY IN SILICO INVESTIGATIONS

2020 ◽  
pp. 52-57
Author(s):  
ABDIRAHMAN ELMI ◽  
S. AL-JAWAD SAYEM ◽  
MOHAMED AHMED ◽  
FATOUMA ABDOUL-LATIF
Keyword(s):  
Medicinal Plants ◽  
Natural Compounds ◽  
Binding Energies ◽  
Pharmacokinetic Parameters ◽  
Global Pandemic ◽  
Main Protease ◽  
Target Sites ◽  
Better Than

Objective: The new coronavirus type SARS-Cov 2 (severe acute respiratory syndrome), which appeared in autumn 2019 in China, became a global pandemic in a few months. In this work, we looked for the potential anti SARS-Cov 2 of the compounds isolated from three Djiboutian medicinal plants, namely Acacia seyal, Cymbopogon commutatus, and Indigofera caerulea. Methods: We carried out a molecular docking with nine biomolecules, β-Sitosterol, Quercetin, Catechin, Lupeol, Rutin, Kaempferol, Gallic acid, Piperitone and Limonene on three target sites which are SARS-CoV-2 main protease (Mp), SARS-CoV-2 receptor-binding domain (RBD) and human furin protease. These targets are chosen because of their role in the process of penetration of the virus into human cells and its multiplication. Moreover, the predictions of pharmacokinetic parameters as well as toxicological properties have been determined using an online bioinformatics tool named SwissADME and AdmetSAR respectively. Results: The phenolic compounds have a very good affinity on these three target sites with binding energies of up to-9.098 kcal/mol for rutin on SARS-CoV-2 Mp, much better than the two reference drugs hydroxychloroquine (-5.816 kcal/mol) and remdesivir (-7.194 kcal/mol). Except for β-Sitosterol, the tested biomolecules have weak toxicity. Conclusion: These natural compounds can be used against covid 19 pending In vitro and In vivo evaluations.

Sign in / Sign up

Export Citation Format

Share Document