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 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 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 Alkaloids from Cryptolepis sanguinolenta as Potential Inhibitors of SARS-CoV-2 Viral Proteins: An In Silico Study

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Lawrence Sheringham Borquaye ◽  
Edward Ntim Gasu ◽  
Gilbert Boadu Ampomah ◽  
Lois Kwane Kyei ◽  
Margaret Amerley Amarh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Rna Polymerase ◽  
In Silico ◽  
Viral Proteins ◽  
Binding Energies ◽  
New Drugs ◽  
Binding Potential ◽  
Rna Dependent Rna Polymerase ◽  
Cryptolepis Sanguinolenta ◽  
Main Protease

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.

scholarly journals Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment

2020 ◽  
Author(s):  
Varalakshmi Velagacherla ◽  
Akhil Suresh ◽  
Chetan H Mehta ◽  
Yogendra Nayak ◽  
Usha Y Nayak
Keyword(s):  
Md Simulations ◽  
Viral Proteins ◽  
Spike Protein ◽  
Protein Targets ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Multiple Protein ◽  
Approved Drugs ◽  
Viral Target ◽  
Selection Of

Abstract Background: Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is now a pandemic which began in Wuhan province of China. Drug discovery teams around the globe are in a race to develop a medicine for its management. For a novel molecule to enter into the market it takes time and the ideal way is to exploit the already approved drugs and repurpose them to use therapeutically.Methods: In this work, we have attempted to screen selected molecules that have shown an affinity towards multiple protein targets of COVID-19 using Schrödinger suit. Molecules were selected from approved antiviral, anti-inflammatory or immunomodulatory classes. The viral proteins selected were angiotensin-converting enzyme 2 (ACE2), main protease (Mpro) and spike protein. Computational tools such as molecular docking, prime MM-GBSA, induced-fit docking (IFD) and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins.Results: The ligand-binding stability for the viral proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro) and 6M1D (ACE2), was in the order of Nintedanib>Quercetin, Nintedanib>Darunavir, Nintedanib> Baricitinib respectively. The MM-GBSA, IFD, and MD simulation studies infer that the drug nintedanib has the highest binding stability among the shortlisted molecules towards the selected viral target proteins. Conclusion: Nintedanib, which is primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing and used in the management of COVID-19.

scholarly journals Potential RNA-dependent RNA polymerase inhibitors as prospective therapeutics against SARS-CoV-2

2020 ◽  
Vol 69 (6) ◽  
pp. 864-873 ◽  
Author(s):  
Rudramani Pokhrel ◽  
Prem Chapagain ◽  
Jessica Siltberg-Liberles
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Species Barrier ◽  
Rna Dependent Rna Polymerase ◽  
Virtual Screen ◽  
The Us ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics. Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication. Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen. Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects. Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

scholarly journals Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1166
Author(s):  
Krishnaprasad Baby ◽  
Swastika Maity ◽  
Chetan H. Mehta ◽  
Akhil Suresh ◽  
Usha Y. Nayak ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Active Site ◽  
In Silico ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Rna Dependent Rna Polymerase ◽  
Target Proteins ◽  
Dynamics Simulations ◽  
Preclinical And Clinical Studies ◽  
And Control

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (Mpro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.

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 How Fast Fast-Folding Proteins Fold in Silico

2016 ◽  
Author(s):  
Yuan-Ping Pang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
In Silico ◽  
Genetic Information ◽  
Computer Algorithms ◽  
Biological Functions ◽  
Different Temperatures ◽  
Experimental Values ◽  
Folding Simulations ◽  
Dynamics Simulations

AbstractIn reported microcanonical molecular dynamics simulations, fast-folding proteins CLN025 and Trp-cage autonomously folded to experimentally determined native conformations. However, the folding times of these proteins derived from the simulations were more than 4–10 times longer than their experimental values. This article reports autonomous folding of CLN025 and Trp-cage in isobaric–isothermal molecular dynamics simulations with agreements within factors of 0.69–1.75 between simulated and experimental folding times at different temperatures. These results show that CLN025 and Trp-cage can now autonomously fold in silico as fast as in experiments, and suggest that the accuracy of folding simulations for fast-folding proteins begins to overlap with the accuracy of folding experiments. This opens new prospects of developing computer algorithms that can predict both ensembles of conformations and their interconversion rates for a protein from its sequence for artificial intelligence on how and when a protein acts as a receiver, switch, and relay to facilitate various subcellular-to-tissue communications. Then the genetic information that encodes proteins can be better read in the context of intricate biological functions.

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