COVID-19 Main Protease Inhibitors Research Articles

Natural products as inhibitors of COVID-19 main protease–A virtual screening by molecular docking

Background: The novel coronavirus (2019-nCoV) causes a severe respiratory illness unknown to a human before. Its alarmingly quick transmission to many countries across the world has resulted in a global health emergency. Therefore, an imminent need for drugs to combat this disease has been increased. Worldwide collaborative efforts from scientists are underway to determine a therapy to treat COVID-19 infections and reduce mortality rates. Since herbal medicines and purified natural products have been reported to have antiviral activity against Coronaviruses (CoVs), this in silico evaluation was performed for identifying potential natural compounds with promising inhibitory activities against COVID-19. Methods: In this study, a High Throughput Virtual Screening (HTVS) protocol was used as a fast method for discovering novel drug candidates as potential COVID-19 main protease (Mpro) inhibitors. Over 180,000 natural product-based compounds were obtained from the ZINC database and virtually screened against the COVID-19 Mpro. In this study, the Glide docking program was applied for high throughput virtual screening. Also, Extra precision (XP) has been used following the induced-fit docking (IFD) approach. The ADME properties of all compounds were analyzed and a final selection was made based on the Lipinski rule of five. Also, molecular dynamics (MD) simulations were conducted for a virtual complex of the best scoring compound with COVID-19 protease. Results: Nineteen compounds were introduced as new potential inhibitors. Compound ZINC08765174 (1-[3-(1H-indol-3-yl) propanoyl]-N-(4-phenylbutan-2-yl)piperidine-3-carboxamide showed a strong binding affinity (-11.5 kcal/mol) to the COVID-19 Mpro comparing to peramivir (-9.8 kcal/mol) as a positive control. Conclusions: Based on these findings, nineteen compounds were proposed as possible new COVID-19 inhibitors, of which ZINC08765174 had a high affinity to Mpro. Furthermore, the promising ADME properties of the selected compounds emphasize their potential as attractive candidates for the treatments of COVID-19.

In silico Approach on Ribavirin Inhibitors for COVID-19 Main Protease

It has been well-known that COVID-19 has serious negative impacts on all sides of human life worldwide since the end of the year 2019, and exploring possible treatments for it is a must. To this aim, this computer-based in silico work was performed to investigate the impact of structural modification of Ribavirin (RBV) on its potential interaction with the COVID-19 main protease (MPO). Fourteen RBV compounds, including the original RBV and thirteen modified structures regarding the triazole ring, were investigated in this work based on quantum computations of structural chemistry features and molecular docking simulations (MDs) of RBV…MPO complex formations. Interestingly, six compounds were better than the original RBV for potent interaction with the MPO target, in which R08 (-NH2) was the best one among fourteen compounds. In conclusion, modification of RBV raised binding affinity against the COVID-19 MPO target.

ADME predictions and molecular docking study of some compounds and drugs as potential inhibitors of COVID-19 main protease: A virtual study as comparison of computational results

There is an urgent need for a drug to be used against COVID-19, which negatively affects human life worldwide and causes pandemic leading to the death of many people. Although some drugs are included in the treatment protocols of health institutions, there are currently no specific drugs against COVID-19 or are unknown, and effective treatment options remain very limited. Since designing a novel drug and testing its pharmacological properties may take long years, here we used a faster virtual study approach for some of our compounds with different chemical structures against COVID-19. Moreover, we included some drugs in this study and compared in silico results obtained. The activity potentials of these compounds were further evaluated through molecular docking studies with AutoDock4 and AutoDock Vina software. Among all the compounds studied, compounds 1a, 1b, and 1c demonstrate significant activity like other prodrugs, particularly against COVID-19. The most promising compound 1a has appropriate ADME prediction values and high binding affinity as a potential inhibitor of COVID-19 main protease.

Molecular Docking Study of Primaquine-Favipiravir Based Compounds as Potential Inhibitors of COVID-19 Main Protease

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Rational Approach towards COVID-19 Main Protease Inhibitor (Fexofenadine) Via Molecular Docking

Rational Approach towards COVID-19 Main Protease Inhibitor (Fexofenadine) Via Molecular Docking

Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies.

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today's diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation

In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS (https://www.ebi.ac.uk/merops/index.shtml). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.

Finding potent inhibitors for COVID-19 main protease (Mpro): an in silico approach using SARS-CoV-3CL protease inhibitors for combating CORONA

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computer-aided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against Mpro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials. Communicated by Ramaswamy H. Sarma

Screening of plant-based natural compounds as a potential COVID-19 main protease inhibitor: an in silico docking and molecular dynamics simulation approach

A new strain of coronavirus (CoV) has been identified as SARS-CoV-2, which is responsible for the recent COVID-19 pandemic. Currently, there is no approved vaccine or drug available to combat the pandemic. COVID-19 main protease (Mpro) is a key CoV enzyme, which plays an important role in triggering viral replication and transcription, turns it into an attractive target. Therefore, we aim to screen natural products library to find out potential COVID-19 Mpro inhibitors. Plant-based natural compounds from Sigma-Aldrich plant profiler chemical library have been screened through virtual molecular docking and molecular dynamics simulation to identify potential inhibitors of COVID Mpro. Our virtual molecular docking results have shown that there are twenty-eight natural compounds with a greater binding affinity toward the COVID-19 Mpro inhibition site as compared to the co-crystal native ligand Inhibitor N3 (-7.9 kcal/mol). Also, molecular dynamics simulation results have confirmed that Peonidin 3-O-glucoside, Kaempferol 3-O-β–rutinoside, 4-(3,4-Dihydroxyphenyl)-7-methoxy-5-[(6-O-β-D-xylopyranosyl-β-D-glucopyranosyl)oxy]-2H-1-benzopyran-2-one, Quercetin-3-D-xyloside, and Quercetin 3-O-α-L-arabinopyranoside (selected based on the docking score) possess a significant amount of dynamic properties such as stability, flexibility and binding energy. Our In silco results suggests that all the above mention natural compounds have the potential to be developed as a COVID-19 Mpro inhibitor. But before that, it must go through under the proper preclinical and clinical trials for further scientific validation. Communicated by Ramaswamy H. Sarma

Amoxicillin and Clavulanate as Potential Multiple Effect Inhibitors of 2019 Novel Coronavirus Main Protease and RNA-Dependent RNA Polymerase with Strong Receptor-Binding Domain (RBD), Molecular Docking and SAR Study

SARS-CoV-2 is a novel coronavirus was isolated and identified first time in 2019 in Wuhan, China. Nowadays, it is a worldwide danger and the WHO named it as a pandemic. With a number of 5,593,631 as confirmed cases, and 353,334 as deaths. On 17 February, we have started our researches for finding potential inhibitors for COVID-19 main protease, especially after publishing the first crystalline structure of this protein in the PDB with PDB ID: 6lu7. We have found three potent molecules Hispidin, Folic acid and Lepidine E with Ki values 5.21, 3.71 and 1.89 μM respectively. Continuing the same context and in order to determine more inhibitors as potential strategy for COVID-19 treatment by molecular docking. We detected Amoxicillin and clavulanate as very strong inhibitors with a rate of 100% to the nCov-19 main protease and RNA-dependent RNA polymerase by several hydrogen bonds and hydrophobic interactions. In addition, we have docked both inhibitors to Spike protein domain of the virus responsible for its binding to the ACE2 receptors in the lungs and other vital organs. The results show that the ligands bound tightly with this latter confirming multiple effect and target of the drugs. Funding Statement: DGRSDT of Algeria Declaration of Interests: None to declare Ethics Approval Statement: Not needed

Virtual screening, molecular docking studies and DFT calculations of FDA approved compounds similar to the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed as the causative virus of COVID-19 disease, which is currently a worldwide pandemic. Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is one of the most potent chemical compounds proposed to treat COVID-19 infection. We, therefore, performed virtual screening on FDA approved drugs that are similar to the efavirenz moiety. Subsequently, the compounds were subjected to screening by analyzing their drug-likeness, such as Lipinski's rule of five and ADMET properties. Molecular docking study revealed that Met165, His41, His163, and Phe140 were important interacting residues for COVID-19 main protease receptor-ligand interaction. Five top-ranked compounds, podophyllotoxin, oxacillin, lovastatin, simvastatin, and gefitinib, were selected by virtual screening and docking studies. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO) and energy gap values was calculated using density functional theory (DFT). The results of the study showed that lovastatin and simvastatin might be considered as lead compounds for further development for COVID-19 main protease inhibitors.

In-Silico approach for identification of effective and stable inhibitors for COVID-19 main protease (Mpro) from flavonoid based phytochemical constituents of Calendula officinalis

The recent outbreak of the coronavirus disease COVID-19 is putting the world towards a great threat. A recent study revealed COVID-19 main protease (Mpro) is responsible for the proteolytic mutation of this virus and is essential for its life cycle. Thus inhibition of this protease will eventually lead to the destruction of this virus. In-Silico Molecular docking was performed with the Native ligand and the 15 flavonoid based phytochemicals of Calendula officinals to check their binding affinity towards the COVID-19 main protease. Finally, the top 3 compounds with the highest affinity have been chosen for molecular dynamics simulation to analyses their dynamic properties and conformational flexibility or stability. In-Silico Docking showed that major phytochemicals of Calendula officinals i.e. rutin, isorhamnetin-3-O-β-D, calendoflaside, narcissin, calendulaglycoside B, calenduloside, calendoflavoside have better binding energy than the native ligand (inhibitor N3). MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compare to Mpro-native ligand (inhibitor N3) complex. Overall, rutin and caledoflaside showed better stability, compactness, and flexibility. Our in silico (Virtual molecular docking and Molecular dynamics simulation) studies pointed out that flavonoid based phytochemicals of calendula (rutin, isorhamnetin-3-O-β-D, calendoflaside) may be highly effective for inhibiting Mpro which is the main protease for SARS-CoV-2 causing the deadly disease COVID-19. Rutin is already used as a drug and the other two compounds can be made available for future use. Thus the study points a way to combat COVID-19 by the use of major flavonoid based phytochemicals of Calendula officinals. Communicated by Ramaswamy H. Sarma

Virtual screening based on molecular docking of possible inhibitors of Covid-19 main protease

Coronavirus (COVID-19) is an enveloped RNA virus that is diversely found in humans and that has now been declared a global pandemic by the World Health Organization. Thus, there is an urgent need to develop effective therapies and vaccines against this disease. In this context, this study aimed to evaluate in silico the molecular interactions of drugs with therapeutic indications for treatment of COVID-19 (Azithromycin, Baricitinib and Hydroxychloroquine) and drugs with similar structures (Chloroquine, Quinacrine and Ruxolitinib) in docking models from the SARS-CoV-2 main protease (M-pro) protein. The results showed that all inhibitors bound to the same enzyme site, more specifically in domain III of the SARS-CoV-2 main protease. Therefore, this study allows proposing the use of baricitinib and quinacrine, in combination with azithromycin; however, these computer simulations are just an initial step for conceiving new projects for the development of antiviral molecules.

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences

SARS-CoV-2 (2019-nCoV) emerged in 2019 and proliferated rapidly across the globe. Scientists are attempting to investigate antivirals specific to COVID-19 treatment. The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease (Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates. So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity. With the aid of in silico techniques such as molecular docking and druggability studies, we have proposed several natural active compounds including glycyrrhizin, bicylogermecrene, tryptanthrine, β-sitosterol, indirubin, indican, indigo, hesperetin, crysophanic acid, rhein, berberine and β-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2. Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.Graphic

Favipiravir May Acts as COVID-19 Main Protease PDB ID 6LU7 Inhibitor: Docking Analysis

Coronavirus is a well-known threat to the human being in the form of COVID-19. Virus replication may be controlled by inhibition of protease enzyme. Hence, well known 13 antiviral drugs have been observed by docking analysis for understanding the binding pattern of drugs with COVID-19 main protease PDB ID: 6LU7 for any possibilities of protease inhibition. For docking analysis PyRx- Python Prescription 0.8 was used. This analysis reveals that the essential amino acids involved in binding of antiviral drugs to COVID-19 main protease PDB ID: 6LU7 are Glycine (Gly), Serine (Ser), Cysteine (Cys), Leucine (Leu), Asparagine (Asn), Glutamine (Gln), Glutamic acid (Glu) and Threonine (Thr). After docking analysis, it was observed that Favipiravir maybe act as COVID-19 main protease inhibitor despite being vRNA polymerase inhibitor and may further be used in the treatment of COVID-19 infection.

In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) from Natural Products

In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) from Natural Products

Hydroxychloroquine as Potent Inhibitor of COVID -19 Main Protease: Grid Based Docking Approach

Objectives: Coronavirus (COVID-19) is an enveloped RNA virus that occurs in various forms in humans and wildlife. A total of six disease-causing species have been identified in humans. Viral infections play a vital role in human diseases, and recent outbreaks have developed globally in the form of novel corona. The SS-RNA virus from the enveloped coronavirus family caused SARS (Severe Acute Respiratory Syndrome), a life-threatening viral infection. In many countries around the world, the spread of infection is rapid. As of March 26, 2020, there were 462.684 confirmed cases globally, and 20.834 deaths were recorded. The World Health Organization (WHO) described COVID-19 as a pandemic on March 11, 2020. There are numerous drug trials going on with some positive results. However, since no vaccine is available, the best way to combat the virus is to use preventive methods. Methods: In this study, an attempt was made to find the new COVID-19 main protease inhibitor with a molecular docking approach. A grid-based docking approach was chosen to find the binding using VLife MDS software. The 2D structure of the compounds was created and then converted into the 3D, and then, it was energetically minimized up to the RMS gradient of 0.01, using the Merck Molecular Force Field (MMFF). By using cavity determination option, the enzyme’s cavities were determined. Cavity no.1 was selected for docking. The active site for docking was defined as all atoms within 5A? radius. Results: Hydroxychloroquine is a slow-acting antirheumatic drug. The value of hydroxychloroquine is analogous to that reported for other disease-modifying anti-rheumatic drugs. The docking score obtained was -4.308880 and the number of receptor atoms was 77, while the number of ligand atoms was 20, which shows that hydroxychloroquine binds effectively with Covid-19 protease. Conclusion: Hydroxychloroquine was taken as drug following Lipinski’s rule of five, so it had a very good drug score and drug-likeness score as well. This study reveals that Hydroxychloroquine has good binding affinity with COVID-19 protease and thus can be used as prophylaxis and therapeutic treatment for corona patients. Keywords: COVID-19, Hydroxychloroquine, Molecular Docking & Prevention measures

Molecular Docking Studies of Some Natural Products Against SARS-CoV-2 Main Protease: Potential Therapeutic Agents for COVID-19

The severe form of respiratory disease (COVID-19), caused by SARS-COV-2 virus, has evolved into a pandemic is the defining global health crisis of our time and greatest challenge we have faced since second World War. Hence, the current situation demands an immediate need to explore all the possible therapeutic strategies that can be control spread of the diseases. We identified potent COVID-19 Mpro inhibitors based on molecular docking studies on 24 known antiviral natural compounds, which are from medicinal plants and marine sponges. The results revealed that 15 potential COVID-19 main protease inhibitors have been identified among the 24 natural compounds of plants and marine origin. The result further revealed that the selected natural products that has lower free binding energy is Halituline (-8.41 Kcal/mol). As these active compounds were extensively validated by molecular docking, the chance that at least few of these compounds could be bioactive is excellent.