Secondary Metabolites from Caulerpa Cylindracea (Sonder) Could Be Alternative Natural Antiviral Compounds for COVID-19: A Further in Silico Proof

SARS-CoV-2 has been exhibiting extremely spreading property all around the world since its existence from Wuhan-China in December-2019. Although it has caused a death toll of over than 1.3 M people, no validated vaccine has been proposed yet. On the other hand, very dense studies on the vaccine development have been carrying out in some countries such as the US, Germany, UK, China and Russia. Due to side effects of current antiviral agents used in the therapy of COVID-19, there is a great need for the development of alternative compounds for this disease. Caulerpin (CPN) and caulerpenyne (CYN), predominant natural secondary metabolites from invasive marine green algae Caulerpa cylindracea,are proposed to neutralize the virus from two targets: spike protein (5XLR) and main protease (6YB7) in this study. The results show that the binding energies related to CPN-6YB7 and CYN-6YB7 interactions are found to be -8.02 kcal/mol and -6.83 kcal/mol, respectively. The binding energies were -9.68 kcal/mol and -7.53 kcal/mol, respectively, for CPN-5XLR and CYN-5XLR. In the molecular dynamics results, RMSD values show that CPN and CYN can form stable complexes with the proteins where CYN is more stable with 6YB7 and CPN interacts better with 5XLR. These differences seem to be based on the type of interactions of the complexes. In conclusion, caulerpin and caulerpenyne can further be investigated experimentally for their anti-SARS-CoV-2 efficiency.

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Secondary Metabolites from Caulerpa Cylindracea (Sonder) Could Be Alternative Natural Antiviral Compounds for COVID-19: A Further in Silico Proof

10.26434/chemrxiv.13353473 ◽

2020 ◽

Author(s):

Levent Çavaş ◽

Cengizhan Dag ◽

Miguel Carmena-Bargueño ◽

Carlos Martínez-Cortés ◽

José Pedro Cerón-Carrasco ◽

...

Keyword(s):

Secondary Metabolites ◽

Vaccine Development ◽

Antiviral Agents ◽

Binding Energies ◽

Antiviral Compounds ◽

Main Protease ◽

The Us ◽

The World ◽

Molecular Dynamics Results ◽

Spreading Property

SARS-CoV-2 has been exhibiting extremely spreading property all around the world since its existence from Wuhan-China in December-2019. Although it has caused a death toll of over than 1.3 M people, no validated vaccine has been proposed yet. On the other hand, very dense studies on the vaccine development have been carrying out in some countries such as the US, Germany, UK, China and Russia. Due to side effects of current antiviral agents used in the therapy of COVID-19, there is a great need for the development of alternative compounds for this disease. Caulerpin (CPN) and caulerpenyne (CYN), predominant natural secondary metabolites from invasive marine green algae Caulerpa cylindracea,are proposed to neutralize the virus from two targets: spike protein (5XLR) and main protease (6YB7) in this study. The results show that the binding energies related to CPN-6YB7 and CYN-6YB7 interactions are found to be -8.02 kcal/mol and -6.83 kcal/mol, respectively. The binding energies were -9.68 kcal/mol and -7.53 kcal/mol, respectively, for CPN-5XLR and CYN-5XLR. In the molecular dynamics results, RMSD values show that CPN and CYN can form stable complexes with the proteins where CYN is more stable with 6YB7 and CPN interacts better with 5XLR. These differences seem to be based on the type of interactions of the complexes. In conclusion, caulerpin and caulerpenyne can further be investigated experimentally for their anti-SARS-CoV-2 efficiency.

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Current Trends in SPR Biosensing of SARS-CoV-2 Entry Inhibitors

Chemosensors ◽

10.3390/chemosensors9120330 ◽

2021 ◽

Vol 9 (12) ◽

pp. 330

Author(s):

Elba Mauriz ◽

Laura M. Lechuga

Keyword(s):

High Throughput Screening ◽

Antiviral Agents ◽

Host Cells ◽

Binding Affinities ◽

Entry Inhibitors ◽

Antiviral Compounds ◽

Current Trends ◽

Main Protease ◽

Emerging Risk ◽

Repurposed Drugs

The emerging risk of viral diseases has triggered the search for preventive and therapeutic agents. Since the beginning of the COVID-19 pandemic, greater efforts have been devoted to investigating virus entry mechanisms into host cells. The feasibility of plasmonic sensing technologies for screening interactions of small molecules in real time, while providing the pharmacokinetic drug profiling of potential antiviral compounds, offers an advantageous approach over other biophysical methods. This review summarizes recent advancements in the drug discovery process of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) inhibitors using Surface Plasmon Resonance (SPR) biosensors. A variety of SPR assay formats are discussed according to the binding kinetics and drug efficacies of both natural products and repurposed drugs. Special attention has been given to the targeting of antiviral agents that block the receptor binding domain of the spike protein (RBD-S) and the main protease (3CLpro) of SARS-CoV-2. The functionality of plasmonic biosensors for high-throughput screening of entry virus inhibitors was also reviewed taking into account experimental parameters (binding affinities, selectivity, stability), potential limitations and future applications.

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In silico Repositioning for Dual Inhibitor Discovery of SARS-CoV-2 (COVID-19) 3C-like Protease and Papain-like Peptidase

10.20944/preprints202004.0084.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kowsar Bagherzadeh ◽

Kourosh Daneshvarnejad ◽

Mohammad Abbasinazari ◽

homa azizian

Keyword(s):

Active Sites ◽

Reproduction Number ◽

Antiviral Agents ◽

Binding Energies ◽

Dual Inhibitor ◽

Main Protease ◽

Inhibitor Discovery ◽

Dual Inhibitors ◽

Dual Inhibition ◽

Novel Coronavirus

Aims: In late December 2019, early reports predicted the onset of a potential Coronavirus outbreak in china, given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19). Because of high ability of transmission and widespread prevalence, the mortality of COVID-19 infection is growing fast worldwide. Absent of an anti-COVID-19 has put scientists on the urge to repurpose already approved therapeutics or to find new active compounds against coronavirus. Here in this study, a set of computational approaches were performed in order to repurpose antivirals for dual inhibition of the frontier proteases involved in virus replication, papain-like protease (PLpro; corresponding to nsp3) and a main protease (Mpro), 3C‑like protease (3CLpro; corresponding to nsp5). Materials and Methods: In this regard, a rational virtual screening procedure including exhaustive docking techniques was performed for a database of 160 antiviral agents over 3CLpro and PLpro active sites of SARS-CoV-2. The compounds binding energies and interaction modes over 3CLpro and PLpro active sites were analyzed and ranked with the aid of free Gibbs binding energy. The most potent compounds, based on our filtering process, are then proposed as dual inhibitors of SARSC-CoV-2 proteases. Key findings: Accordingly, seven antiviral agents including two FDA approved (Nelfinavir, Valaganciclovir) and five investigational compounds (Merimepodib, Inarigivir, Remdesivir, Taribavirine and TAS106-106) are proposed as potential dual inhibitors of the enzymes necessary for RNA replication in which Remdesivir as well as Inagrivir have the highest binding affinity for both of the active sites. Significance: The mentioned drug proposed to inhibit both PLpro and 3CLpro enzymes with the aim of finding dual inhibitors of SARSC-CoV-2 proteases.

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Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

Biology ◽

10.3390/biology10050389 ◽

2021 ◽

Vol 10 (5) ◽

pp. 389

Author(s):

Sameh S. Elhady ◽

Reda F. A. Abdelhameed ◽

Rania T. Malatani ◽

Abdulrahman M. Alahdal ◽

Hanin A. Bogari ◽

...

Keyword(s):

Molecular Docking ◽

Md Simulation ◽

Protein Complexes ◽

Antiviral Agents ◽

Binding Energies ◽

Dynamics Simulation ◽

Main Protease ◽

Simulation Parameters ◽

Molecular Docking And Dynamics ◽

Dual Target

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.

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Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

10.21203/rs.3.rs-102884/v1 ◽

2020 ◽

Author(s):

Shravan Kumar Gunda ◽

Hima Kumari P ◽

Gourav Choudhir ◽

Anuj Kumar ◽

P B. Kavi Kishor ◽

...

Keyword(s):

Molecular Docking ◽

Antiviral Agents ◽

Binding Energies ◽

Dynamics Simulation ◽

Lipinski’S Rule ◽

Drug Candidates ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Dynamics Simulations ◽

Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

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Docking Studies of Usnic Acid and Sodium Usnate on SARS CoV-2 Main Protease and Spike Protein RBD

10.26434/chemrxiv.12638906 ◽

2020 ◽

Author(s):

Roopa Guthappa

Keyword(s):

Infectious Disease ◽

Antiviral Agents ◽

Usnic Acid ◽

Docking Studies ◽

Spike Protein ◽

Binding Affinities ◽

Herbal Supplements ◽

Main Protease ◽

The World ◽

Mouth Wash

SARS CoV-2 a pandemic influenza like infectious disease emerged in December 2019 has spread throughout the world within few months. Scientists are trying their best to find medicine and vaccine. Usnic acid and its derivatives as herbal supplements are widely used as mouth wash, cosmetics, antiviral agents. In this study, usnic acid and its derivative-sodium usnate in comparison with favipiravir are docked with main protease and spike protein RBD 6M0J of SARS Cov-2. Usnic acid and sodium usnate exhibit better binding affinities for main protease and spike RBD. The data has been compared with favipiravir. Favipiravir, usnic acid, sodium usnate shows binding affinity of -4.25, -8.05 and -8.55 kcal/mol respectively with main protease. While favipiravir, usnic acid and sodium usnate exhibit binding affinities of -4.25, -6.02 and -6.53 kcal/mol with spike RBD respectively. One of the interesting features is that the inhibition constant values of usnic acid is 1.27 µM and sodium usnate is 539.86 nM in comparison to favipiravir (764.13 µM) with main protease.

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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease

Biochemical Journal ◽

10.1042/bcj20210197 ◽

2021 ◽

Vol 478 (13) ◽

pp. 2499-2515 ◽

Cited By ~ 2

Author(s):

Jennifer C. Milligan ◽

Theresa U. Zeisner ◽

George Papageorgiou ◽

Dhira Joshi ◽

Christelle Soudy ◽

...

Keyword(s):

Economic Effects ◽

Calpain Inhibitor ◽

Chemical Library ◽

Antiviral Compounds ◽

Main Protease ◽

The World ◽

Ic50 Values ◽

Global Population ◽

Micromolar Range

The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.

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Effectiveness of Natural Antioxidants against SARS-CoV-2? Insights from the In-Silico World

Antibiotics ◽

10.3390/antibiotics10081011 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1011

Author(s):

Muhammad Fayyaz ur Rehman ◽

Shahzaib Akhter ◽

Aima Iram Batool ◽

Zeliha Selamoglu ◽

Mustafa Sevindik ◽

...

Keyword(s):

Molecular Docking ◽

Protein Interactions ◽

Dissociation Constants ◽

Antiviral Agents ◽

Natural Antioxidants ◽

Md Simulations ◽

Binding Energies ◽

Protein Targets ◽

Docking Simulations ◽

Main Protease

The SARS CoV-2 pandemic has affected millions of people around the globe. Despite many efforts to find some effective medicines against SARS CoV-2, no established therapeutics are available yet. The use of phytochemicals as antiviral agents provides hope against the proliferation of SARS-CoV-2. Several natural compounds were analyzed by virtual screening against six SARS CoV-2 protein targets using molecular docking simulations in the present study. More than a hundred plant-derived secondary metabolites have been docked, including alkaloids, flavonoids, coumarins, and steroids. SARS CoV-2 protein targets include Main protease (MPro), Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), Spike glycoprotein (S), Helicase (Nsp13), and E-Channel protein. Phytochemicals were evaluated by molecular docking, and MD simulations were performed using the YASARA structure using a modified genetic algorithm and AMBER03 force field. Binding energies and dissociation constants allowed the identification of potentially active compounds. Ligand-protein interactions provide an insight into the mechanism and potential of identified compounds. Glycyrrhizin and its metabolite 18-β-glycyrrhetinic acid have shown a strong binding affinity for MPro, helicase, RdRp, spike, and E-channel proteins, while a flavonoid Baicalin also strongly binds against PLpro and RdRp. The use of identified phytochemicals may help to speed up the drug development and provide natural protection against SARS-CoV-2.

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Bioinformatic Analysis of Antiviral Medicinal Compounds Against Sars Cov-2 Proteases

Kuwait Journal of Science ◽

10.48129/kjs.splcov.15451 ◽

2021 ◽

Author(s):

Fahad Hassan Shah ◽

◽

Kyeong Ho Lim ◽

Song Ja Kim ◽

◽

...

Keyword(s):

Antiviral Agents ◽

Respiratory Illness ◽

Bioinformatic Analysis ◽

Antiviral Compounds ◽

Medicinal Compounds ◽

Global Pandemic ◽

Viral Proteases ◽

The World ◽

Severe Respiratory Illness ◽

Probable Interaction

The world is under siege from a global pandemic caused by a novel class of coronaviruses called severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). These viruses cause severe respiratory illness leading to death. Molecular studies reveal that SARS CoV-2 proteases are involved in the processing of viral polyproteins. This study was conducted to obtain antiviral agents for SARS CoV-2 proteases. An extensive library of antiviral medicinal compounds was scrutinized to determine the probable interaction with both main and 3-chymotrypsin like proteases. Six antiviral compounds (Abietic Acid, Gallic Acid, Piceatannol, Piperine, Sinomenine, and Triptolide) were capable of establishing hydrogen bonds with the active pocket residues of the viral proteases, with appreciable binding energy. These compounds were subjected to root mean square analysis and tested not only for acute toxicity, but also for absorption, distribution, metabolism, excretion, and toxicity properties. Results were favourable for use in the treatment of SARS COV-2 infection.

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