scholarly journals Flavonoid compounds of buah merah (Pandanus conoideus Lamk) as a potent SARS-CoV-2 main protease inhibitor: in silico approach

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abd. Kakhar Umar
Keyword(s):  
Protein Interactions ◽  
In Silico ◽  
Antiviral Drug ◽  
Pharmacokinetic Profile ◽  
Unbound Fraction ◽  
Receptor Complexes ◽  
Flavonoid Compounds ◽  
Global Pandemic ◽  
Main Protease ◽  
Low Toxicity

Abstract Background COVID19 is a global pandemic that threatens all nations. As there is no effective antiviral drug for COVID19, we examined the potency of natural ingredients against the SARS-CoV-2 main protease (PDB ID 6YNQ). Buah merah is a typical fruit from Papua, Indonesia, which is known to contain high levels of carotenoids and flavonoids. The contents have been proven to be effective as antiparasitic and anti-HIV. An in silico approach to 16 metabolites of buah merah (Pandanus conoideus Lamk) was carried out using AutoDock Vina. Furthermore, the study of the dynamics of ligand–protein interactions was carried out using CABS Flex 2.0 server to determine the test ligand and receptor complexes' stability. ADMET prediction was also carried out to study the pharmacokinetic profile of potential antiviral candidates. Result The docking results showed that 3 of the 16 buah merah metabolites were potent inhibitors against the SARS-CoV-2 main protease. The flavonoid compounds are quercetin 3′-glucoside, quercetin 3-O-glucose, and taxifolin 3-O-α-arabinopyranose with a binding affinity of − 9.7, − 9.3, and − 8.8, respectively, with stable ligand–protein complex. ADMET study shows that the three compounds are easily dissolved, easily absorbed orally and topically, have a high unbound fraction, low toxicity, and non-irritant. Conclusion We conclude that quercetin 3′-glucoside, quercetin 3-O-glucose, and taxifolin 3-O-α-arabinopyranose can be used and improved as potential anti-SARS-CoV-2 agents in further study.

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals In Silico Exploration of Repurposing and Optimizing Traditional Chinese Medicine Rutin for Possibly Inhibiting SARS-CoV-2's Main Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Haoran Wang ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
In Silico ◽  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
Viral Proteins ◽  
Biological Functions ◽  
Rna Dependent Rna Polymerase ◽  
Global Pandemic ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Viral Target

<div>Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines haveb been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the virus have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here,we explore the underlying molecular mechanisms of the computationally determined top candidate–rutin, a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target–Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro’ pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed a more hydrophobic analog which satisfies the rule of five for western medicines and demonstrated that it possesses a much stronger binding affinity to the SARS-COV-2’s Mpro.<br></div>

In Silico Exploration of Molecular Mechanism and Potency Ranking of Clinically Oriented Drugs for Inhibiting SARS-CoV-2’s Main Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
haoran wang ◽  
Binquan Luan
Keyword(s):  
Ligand Binding ◽  
In Silico ◽  
Fast Response ◽  
Binding Mechanism ◽  
Biological Functions ◽  
Drug Molecules ◽  
Global Pandemic ◽  
Main Protease ◽  
Potency Ranking ◽  
High Binding Affinity

<p>Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the binding mechanism between the Mpro's pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. Combining all existing experiment results with our computational ones, we revealed an important ligand-binding mechanism for the Mpro that the binding stability of a ligand inside the Mpro pocket can be significantly improved if the partial ligand occupies the so-called "anchor" site of the Mpro. Along with the high-potent drugs/molecules (such as nelfinavir and curcumin) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro's inhibitors with a high binding affinity. </p>

scholarly journals Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis

2020 ◽  
Vol 72 (6) ◽  
pp. 1553-1561 ◽  
Author(s):  
Krzysztof Marciniec ◽  
Artur Beberok ◽  
Paweł Pęcak ◽  
Stanisław Boryczka ◽  
Dorota Wrześniok
Keyword(s):  
Molecular Docking ◽  
Protein Interactions ◽  
In Silico ◽  
Large Body ◽  
In Silico Analysis ◽  
Molecular Docking Study ◽  
Main Protease ◽  
In Silico Molecular Docking ◽  
First Time ◽  
Positive Controls

Abstract Background A large body of research has focused on fluoroquinolones. It was shown that this class of synthetic antibiotics could possess antiviral activity as a broad range of anti-infective activities. Based on these findings, we have undertaken in silico molecular docking study to demonstrate, for the first time, the principle for the potential evidence pointing ciprofloxacin and moxifloxacin ability to interact with COVID-19 Main Protease. Methods In silico molecular docking and molecular dynamics techniques were applied to assess the potential for ciprofloxacin and moxifloxacin interaction with COVID-19 Main Protease (Mpro). Chloroquine and nelfinavir were used as positive controls. Results We revealed that the tested antibiotics exert strong capacity for binding to COVID-19 Main Protease (Mpro). According to the results obtained from the GOLD docking program, ciprofloxacin and moxifloxacin bind to the protein active site more strongly than the native ligand. When comparing with positive controls, a detailed analysis of the ligand–protein interactions shows that the tested fluoroquinolones exert a greater number of protein interactions than chloroquine and nelfinavir. Moreover, lower binding energy values obtained from KDEEP program were stated when compared to nelfinavir. Conclusions Here, we have demonstrated for the first time that ciprofloxacin and moxifloxacin may interact with COVID-19 Main Protease (Mpro).

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.

scholarly journals In Silico Exploration of Molecular Mechanism and Potency Ranking of Clinically Oriented Drugs for Inhibiting SARS-CoV-2’s Main Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
haoran wang ◽  
Binquan Luan
Keyword(s):  
Ligand Binding ◽  
In Silico ◽  
Fast Response ◽  
Binding Mechanism ◽  
Biological Functions ◽  
Drug Molecules ◽  
Global Pandemic ◽  
Main Protease ◽  
Potency Ranking ◽  
High Binding Affinity

<p>Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the binding mechanism between the Mpro's pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. Combining all existing experiment results with our computational ones, we revealed an important ligand-binding mechanism for the Mpro that the binding stability of a ligand inside the Mpro pocket can be significantly improved if the partial ligand occupies the so-called "anchor" site of the Mpro. Along with the high-potent drugs/molecules (such as nelfinavir and curcumin) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro's inhibitors with a high binding affinity. </p>

scholarly journals Analysis of flavonoid compounds of Orange (Citrus sp.) peel as anti-main protease of SARS-CoV-2: A molecular docking study

2022 ◽  
Vol 951 (1) ◽  
pp. 012078
Author(s):  
N B Maulydia ◽  
T E Tallei ◽  
B Ginting ◽  
R Idroes ◽  
D N illian ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Free Energy ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Flavonoid Compounds ◽  
Global Pandemic ◽  
Main Protease ◽  
New Type ◽  
The City

Abstract SARS-CoV-2 is a new type of coronavirus that causes COVID-19. This virus was first detected in the city of Wuhan, China, at the end of 2019, and until now, it has become a global pandemic. The FDA recently approved Vekluty (remdesivir) for adults and certain pediatric patients who have COVID-19 and are sick enough to require hospitalization. One of the potential drug target candidates for SARS-CoV-2 is the main protease (Mpro). The purpose of this study was to analyze the flavonoid compounds found in orange (Citrus sp.) peel to determine its potential as anti-Mpro through a molecular docking study. The compounds were initially screened for drug-like properties and then docked using Autodock Vina in the PyRx emulator software. The docking results were visualized using the BIOVIA Discovery Visualizer 2020. The result showed that the binding free energy of hesperidin (-8.6 kcal/mol) was higher than nelfinavir (-8.5 kcal/mol). In addition, hesperitin (-7.3 kcal/mol), sakuranetin (-7.1 kcal/mol), isosacuranetin (-7.2 kcal/mol) and tetra-o-methylscutallerin (-6.8 kcal/mol) exhibited lower binding free energy value than control. Based on these results, hesperidin has the potential as an inhibitor of the main protease’s SARS-CoV-2.

scholarly journals Ayurveda botanicals in COVID-19 management: An in silico multi-target approach

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0248479
Author(s):  
Swapnil Borse ◽  
Manali Joshi ◽  
Akash Saggam ◽  
Vedika Bhat ◽  
Safal Walia ◽  
...  
Keyword(s):  
In Silico ◽  
Specific Treatment ◽  
Protective Role ◽  
Tinospora Cordifolia ◽  
Network Pharmacology ◽  
Asparagus Racemosus ◽  
Global Pandemic ◽  
Main Protease ◽  
Short Time Span ◽  
Short Time

The Coronavirus disease (COVID-19) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagious disease. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific antivirals and immunomodulators. Ayurvedic Rasayana therapy has been traditionally used in India for its immunomodulatory and adaptogenic effects, and more recently has been included as therapeutic adjuvant for several maladies. Amongst several others, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) play an important role in Rasayana therapy. The objective of this study was to explore the immunomodulatory and anti SARS-CoV2 potential of phytoconstituents from Ashwagandha, Guduchi and Shatavari using network pharmacology and docking. The plant extracts were prepared as per ayurvedic procedures and a total of 31 phytoconstituents were identified using UHPLC-PDA and mass spectrometry studies. To assess the immunomodulatory potential of these phytoconstituents an in-silico network pharmacology model was constructed. The model predicts that the phytoconstituents possess the potential to modulate several targets in immune pathways potentially providing a protective role. To explore if these phytoconstituents also possess antiviral activity, docking was performed with the Spike protein, Main Protease and RNA dependent RNA polymerase of the virus. Interestingly, several phytoconstituents are predicted to possess good affinity for the three targets, suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would not be adverse herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals as therapeutic adjuvants in the management of COVID-19 following rigorous experimental validation.

scholarly journals In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2082
Author(s):  
Mahmoud A. A. Ibrahim ◽  
Alaa H. M. Abdelrahman ◽  
Tarik A. Mohamed ◽  
Mohamed A. M. Atia ◽  
Montaser A. M. Al-Hammady ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Binding Affinity ◽  
Red Sea ◽  
Protein Interactions ◽  
In Silico ◽  
Target Function ◽  
Pathway Enrichment Analysis ◽  
Main Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.

scholarly journals An in silico study on plant-derived inhibitors against a prognostic Biomarker, Jab1

2019 ◽  
Vol 10 (2) ◽  
pp. 1058-1061
Author(s):  
Fahad Khan ◽  
Pratibha Pandey ◽  
Rashmi Mishra ◽  
Niraj Kumar Jha ◽  
Shweta Sharma
Keyword(s):  
Protein Interactions ◽  
In Silico ◽  
Natural Compounds ◽  
Multiple Protein ◽  
In Silico Study ◽  
Low Toxicity ◽  
Systemic Drug Delivery ◽  
Cancerous Cells ◽  
Systemic Drug

Cancer kills millions of people worldwide every year. The main form of treatment at this point is chemotherapy, which comprises of systemic drug delivery so that they can kill the cancerous cells more effectively. But most of these drugs cause severe side effects in patients and, therefore there is a strong need to focus on identifying natural compounds as a potent phytoinhibitors using various in silico and in vitro approaches. Natural compounds pose low toxicity, hence render them to be an excellent alternative to the basis for the development of new anti-cancerous drugs. Our study considers an effective therapeutic target, Jab1 (c-Jun activation domain-binding protein-1) or a c-Jun coactivator, which has been implicated in multiple protein interactions that play a significant role in various stages of carcinogenesis. Hence we have performed screening of 1500 natural compounds having anticancerous activity by applying various in silico approaches including Lipinski rule of five, ADME, and various Molecular Docking tools. In this study, we have identified two potent phytoinhibitors against Jab1 which needs to be further validated through in vitro approaches.

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