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 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 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>

scholarly journals In Silico Identification and Validation of Organic Triazole Based Ligands as Potential Inhibitory Drug Compounds of SARS-CoV-2 Main Protease

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6199
Author(s):  
Vishma Pratap Sur ◽  
Madhab Kumar Sen ◽  
Katerina Komrskova
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Pharmacokinetic Parameters ◽  
Drug Molecules ◽  
Main Protease ◽  
Ready Availability ◽  
In Silico Identification ◽  
Inhibitory Drug ◽  
High Binding Affinity

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

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>

scholarly journals Novel Coronavirus (SARS-CoV-2) Main Protease: Molecular docking of Puerarin as a Potential inhibitor

2020 ◽  
Author(s):  
Oluwafemi Adeleke Ojo ◽  
Adebola Busola Ojo ◽  
Odunayo Anthonia Taiwo ◽  
Olarewaju M Oluba
Keyword(s):  
Molecular Docking ◽  
Rna Virus ◽  
Drug Candidate ◽  
Lipinski’S Rule ◽  
Global Pandemic ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Novel Coronavirus ◽  
Research World ◽  
High Binding Affinity

Abstract SARS-CoV-2 a single stranded RNA virus which triggered the global pandemic Coronavirus Disease- 2019 (COVID-2019). It has infected about 2,844,712 patients and brought forth mortality rate to about 201,315 among 216 countries as cited by WHO. Drugs including Chloroquine and Hydroxychloroquine derivatives are being administered in most urgent cases; although, with probable side effects to people with metabolic disorders. Thus, unavailability of authorized drugs and treatment for this pandemic demands the research world to discover natural compounds with potency to cure it. This paper assesses the isoflavonoid puerarin from Pueraria lobata as a possible inhibitor of the main protease of SARS-COV-2 (Mpro) via in silico approach, for example molecular docking, Lipinski’s rule of five and toxicity prediction (ADME). Puerarin revealed high binding affinity with the target site of SARS-CoV-2 main protease. This compound slightly meets the criteria of Lipinski’s rule and does not possess properties that could cause adverse effects in humans thus, making puerarin a potential drug candidate to investigate for its usage against COVID-19.

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 In silico Investigation of Tridax procumbens Phyto-Constituents Against SARS-CoV-2 Infection

2021 ◽  
Vol 11 (4) ◽  
pp. 12120-12148
Keyword(s):  
In Silico ◽  
Computational Analysis ◽  
Docking Studies ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Drug Candidates ◽  
Main Protease ◽  
Tridax Procumbens ◽  
Protection Profile ◽  
High Binding Affinity

Tridax procumbens is a popular medicinal plant traditionally used for wound healing and bronchial catarrh. In the current study, in silico computational analysis of 22 active phytoconstituents of T. procumbens was performed against SARS-CoV-2. Molecular Docking studies against six key targets of SARS-CoV-2 including PDB ID: 6LU7, a main protease 3CLpro/Mpro; PDB ID: 6NUR, SARS-Coronavirus NSP12 polymerase bound to NSP7 and NSP8 co-factors, PDB ID: 6m71, SARS-Cov-2 RNA-dependent RNA polymerase (RdRp), PDB ID: 6CS2, SARS Spike Glycoprotein - human ACE2 complex a Stabilized variant; PDB ID: 6VXX, spike glycoprotein of SARS-CoV-2 and its receptor Angiotensin-converting enzyme-2 (PDB ID: 1R42) were accomplished. Additionally, in silico prediction studies using pharmacokinetics (ADMET) properties and the protection profile to identify the paramount drug candidates were also done using online SwissADME and pkCSM web servers. Comprehensive docking analyses confirmed that out of 22 screened phytoconstituents, 6 compounds: Bergenin, beta-Sitosterol, Centaurein, Procumbentin, Luteolin, and Puerarin showed a high binding affinity with studied SARS-CoV-2 target proteins. Pharmacokinetics prediction studies further verified that all selected phytoconstituents were safe with good quality ADMET properties and lacking carcinogenic and tumorigenic properties. Thus, these selected drugs can effectively control COVID-19 and improve immunity, which can be confirmed by further studies.

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 Computational screening of phytocompounds from Moringa oleifera leaf as potential inhibitors of SARS-CoV-2 Mpro

2020 ◽  
Author(s):  
Athira Nair D ◽  
James T J
Keyword(s):  
In Silico ◽  
Methanolic Extract ◽  
Secondary Infection ◽  
Virus Multiplication ◽  
Global Public Health ◽  
Computational Screening ◽  
Global Pandemic ◽  
Main Protease ◽  
Potential Inhibitors

Abstract Background: Coronavirus Disease (COVID-19), caused by novel SARS CoV-2 is rapidly spreading all over the World creating a global public health emergency at unprecedented levels. Till today, no effective treatments or vaccines against this global pandemic is reported and hence to identify lead compounds having potential action in controlling the spread the pandemic is a global concern. This study aimed at in silico screening of phytocompounds from M.oleiera leaf against novel SARS CoV-2 main protease (Mpro) through molecular docking. M.oleiera is an Indian medicinal plant as well as a vegetable, all parts of the plant is medicinally useful and is being used in many of the traditional and Ayurvedic medicinal preparations. Result: When the 19 compounds identified from M.oleifera leaf methanolic extract by Liquid Chromatography Mass Spectrometry (LCMS/MS) analysis and 5 FDA approved anti-viral drugs were screened in silico with SARS CoV-2 main protease (Mpro), the following compounds showed top interaction; apigenin-7-O-rutinoside (-8.8 kcal/mol), Mudanpioside (-8.3 kcal/mol), isoquercetin (-8 kcal/mol), isoquercitrin (-8 kcal/mol), quercetin (-7.8 kcal/mol) and dihydroquercetin (-7.8 kcal/mol). Anti-viral drugs: Raltegravir (-7.2 kcal/mol), Lopinavir-Ritonavir (-7.7 kcal/mol), maraviroc (-8.2 kcal/mol), Nelfinavir (-8.3 kcal/mol) and Tipranavir (-9.2 kcal/mol) also showed active interaction with Mpro. Preliminary phytochemical screening of methanol extract showed the presence of flavonoids, cardiac glycosides, phenols, coumarins, saponins, steroids and phytosteroids. In vitro antioxidant activity of methanolic extract of M.oleifera also showed greater activity, which would ameliorate the post-COVID secondary infection. Conclusion: Hence these compounds from M.oleifera, which are our diet based components, which can interact with the Mpro and curtail COVID-19 virus multiplication in the host cell.

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

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