Rutin: A Potential Antiviral for Repurposing as a SARS-CoV-2 Main Protease (Mpro) Inhibitor

An investigation on dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CLpro) using an in silico approach.

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Promising inhibitors against main protease of SARS CoV-2 from medicinal plants: In silico identification

Acta Pharmaceutica ◽

10.2478/acph-2022-0020 ◽

2021 ◽

Vol 72 (2) ◽

pp. 159-169

Author(s):

OLUWAKEMI EBENEZER ◽

MICHAEL SHAPI

Keyword(s):

Medicinal Plants ◽

Binding Affinity ◽

In Silico ◽

Complex Analysis ◽

Docking Studies ◽

Lipinski’S Rule ◽

Main Protease ◽

Pharmacokinetic Properties ◽

Lipinski’S Rule Of Five ◽

In Silico Identification

Abstract Some compounds reported as active against SARS CoV were selected, and docking studies were performed using the main protease of SARS CoV-2 as the receptor. The docked complex analysis shows that the ligands selectively bind with the target residues and binding affinity of amentoflavone (–10.1 kcal mol–1), isotheaflavin-3’-gallate (–9.8 kcal mol–1), tomentin A and D (–8.0 and –8.8 kcal mol–1), theaflavin-3,3’-digallate (–8.6 kcal mol–1), papyriflavonol A (–8.4 kcal mol–1), iguesterin (–8.0 kcal mol–1) and savinin (–8.3 kcal mol–1) were ranked above the binding affinity of the reference, co-crystal ligand, ML188, a furan-2-carboxamide-based compound. To pinpoint the drug-like compound among the top-ranked compounds, the Lipinski’s rule of five and pharmacokinetic properties of all the selected compounds were evaluated. The results detailed that savinin exhibits high gastrointestinal absorption and can penetrate through the blood-brain barrier. Also, modifying these natural scaffolds with excellent binding affinity may lead to discovering of anti-SARS CoV agents with promising safety profiles.

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Computational Studies Towards Identification of Lead Herbal Compounds of Medicinal Importance for Development of Nutraceutical Against COVID-19

10.26434/chemrxiv.12581819 ◽

2020 ◽

Author(s):

Amit Kumar Srivastav ◽

Sanjeev Kumar Gupta ◽

Umesh Kumar

Keyword(s):

Molecular Docking ◽

In Silico ◽

Md Simulation ◽

Low Cost ◽

Computational Studies ◽

Ramachandran Plot ◽

Lead Compounds ◽

Cryo Electron Microscopy ◽

Main Protease ◽

In Silico Study

In the present study, we have performed the in-silico study of SARS-CoV-2 structure with different herbal compounds of medicinal importance. We selected four <a>viral key proteins of SARS-CoV-2 </a>structure i.e ACE-2 Receptor, Main Protease (Mpro), APO Form, Cryo- electron microscopy structure for the Molecular docking followed by the molecular dynamic simulation. Using this simple in silico approach based on the molecular docking and <a>MD simulation </a>of protein and phytochemicals, we have identified potential lead candidates for the development of low cost nutraceuticals, which can be used against SARS-CoV-2 virus. Our analysis suggested that phytochemicals obtained from Phyllanthus emblica and Azadirachta indica have the highest potential to bind with ACE2 receptor or main protease of SARS-CoV-2, inhibiting the protease enzymatic activity. The lead compounds of herbal origin were docked and simulated on viral key proteins of SARS-CoV-2 structure to evaluate the binding affinity of these phytochemicals along with the type of interaction and its stability in terms of <a>RMSD</a> and <a>Ramachandran plot</a>. Further, these results were also verified by drug likeness properties by using SwissADME software. Overall, our results suggest that out of 14 herbal compounds, Nimbolide and Withaferin-A has great potential to be developed as low-cost nutraceuticals against SARS-CoV-2 virus, which is the need of hour.

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In silico analysis of selected components of grapefruit seed extract against SARS-CoV-2 main protease

The EuroBiotech Journal ◽

10.2478/ebtj-2021-0015 ◽

2021 ◽

Vol 5 (s1) ◽

pp. 5-12

Author(s):

Belmina Saric ◽

Nikolina Tomic ◽

Abdurahim Kalajdzic ◽

Naris Pojskic ◽

Lejla Pojskic

Keyword(s):

Ascorbic Acid ◽

Citric Acid ◽

Gallic Acid ◽

Binding Affinity ◽

In Silico ◽

In Silico Analysis ◽

Seed Extract ◽

First Case ◽

Main Protease ◽

Grapefruit Seed Extract

Abstract At the end of December 2019, first identified cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) started emerging. Ever since the emergence of the first case of infection with SARS-CoV-2 or COVID-19, it became the hottest research topic of numerous studies, in which scientists are trying to understand the path of infection, transmission, replication and viral action, all in order of finding a potential cure or vaccine applying various fundamental principles and methodologies. Using in silico method via AutoDock Vina 1.1.2., we analysed the binding affinity of six selected compounds from grapefruit seed extract (GSE) (narirutin, naringin, naringenin, limonin, ascorbic acid and citric acid) to SARS-CoV-2 main protease Mpro (PDB ID: 6Y84), using acetoside, remdesivir and gallic acid as a positive controls of binding affinity. Results showed highest affinity (rmsd l.b. 0.000; rmsd u.b. 0.000) for narirutin (-10.5), then for naringin (-10.1), acetoside (-10.0), limonin (-9.9), remdesivir (-9.6), naringenin (-8.2), ascorbic acid (-6.7), citric acid (-6.4) and gallic acid (-6.4), all expressed in kcal/mol. Our findings suggest that selected compounds from grapefruit seed extract represent potential inhibitors of SARS-CoV-2 Mpro, but further research is needed as well as preclinical and clinical trials for final confirmation of inhibitory functionality of these compounds.

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Molecular Docking Terhadap Senyawa Kurkumin dan Arturmeron pada Tumbuhan Kunyit (Curcuma Longa Linn.) yang Berpotensi Menghambat Virus Corona

Jurnal e-Biomedik ◽

10.35790/ebm.v9i2.31888 ◽

2021 ◽

Vol 9 (2) ◽

Author(s):

Tiara C. Pradani ◽

. Fatimawali ◽

Aaltje E. Manampiring ◽

Billy J. Kepel ◽

Fona D. Budiarso ◽

...

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Virus Disease ◽

Curcuma Longa ◽

Positive Control ◽

Tropical Plant ◽

Corona Virus ◽

Main Protease ◽

Close Relationship

Abstract: At the end of 2019 the world was shocked by the emergence of a new virus, namely the corona virus (SARS-CoV 2) which is called Corona Virus Disease 2019 or COVID-19. The origin of the emergence of this virus is known to have originated in the city of Wuhan, Hubei Province, China in December 2019.1 Research shows a close relationship with the corona virus that causes Severe Acute Respitatory Syndrome (SARS) which broke out in Hong Kong in 2003, until WHO named it the novel corona virus ( nCoV19). Turmeric (Curcuma longa L.) is a tropical plant that has many benefits and is found in many parts of Indonesia. Turmeric is widely used by the community as a traditional medicine to treat several diseases, such as: anti-inflammatory, antioxidant, hepatoprotective, and others. This study aims to determine the content in several compounds in the turmeric plant that have the potential to inhibit COVID-19 by using the molecular docking method. Using the In Silico method, namely molecular docking with the compounds taken were curcumin and ar-turmerone and the main protease COVID-19 (6LU7). This study obtained the binding affinity of curcumin compounds, namely -7.2 and Ar-turmerone -5.8 compounds against Mpro COVID-19. Remdesivir, which was used as a positive control, had a binding affinity of -7.7. In conclusion, remdesivir got better results compared to curcumin and Ar-turmerone compounds.Keywords: Molecular Docking, Turmeric, COVID-19. Abstrak: Pada akhir tahun 2019 dunia digemparkan dengan munculnya virus baru yaitu corona virus (SARS-CoV 2) yang disebut dengan Corona Virus Disease 2019 atau COVID-19. Awal mula munculnya virus ini diketahui berasal dari Kota Wuhan, Provinsi Hubei, China pada Desember 2019.1 Penelitian menunjukkan hubungan yang dekat dengan virus corona penyebab Severe Acute Respitatory Syndrome (SARS) yang mewabah di Hongkong pada tahun 2003, hingga WHO menamakannya sebagai novel corona virus (nCoV19). Kunyit (Curcuma longa L.) merupakan salah satu jenis tanaman tropis yang banyak memiliki manfaat dan banyak ditemukan di wilayah Indonesia. Kunyit banyak dimanfaatkan masyarakat sebagai obat tradisional untuk mengobati beberapa penyakit seperti: antiinflamasi, antioksidan, hepatoprotektor, dan lain-lain. Penelitian ini bertujuan untuk mengetahui kandungan dalam beberapa senyawa pada tumbuhan kunyit yang berpotensi menghambat COVID-19 dengan metode molecular docking. Menggunakan metode In Silico yaitu molecular docking dengan senyawa yang diambil adalah kurkumin dan ar-Turmerone dan main protease COVID-19 (6LU7). Penelitian ini didapatkan hasil binding affinity senyawa kurkumin yaitu -7.2 dan senyawa ar-turmeron -5.8 terhadap Mpro COVID-19. Remdesivir yang digunakan sebagai control positif mendapatkan hasil binding affinity yaitu -7.7. Sebagai simpulan, remdesivir mendapat hasil yang lebih baik dibandingkan dengan senyawa kurkumin dan ar-turmeron.Kata Kunci: Molecular Docking, Kunyit, COVID-19.

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

Molecules ◽

10.3390/molecules26072082 ◽

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.

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Computational Studies Towards Identification of Lead Herbal Compounds of Medicinal Importance for Development of Nutraceutical Against COVID-19

10.26434/chemrxiv.12581819.v1 ◽

2020 ◽

Author(s):

Amit Kumar Srivastav ◽

Sanjeev Kumar Gupta ◽

Umesh Kumar

Keyword(s):

Molecular Docking ◽

In Silico ◽

Md Simulation ◽

Low Cost ◽

Computational Studies ◽

Ramachandran Plot ◽

Lead Compounds ◽

Cryo Electron Microscopy ◽

Main Protease ◽

In Silico Study

In the present study, we have performed the in-silico study of SARS-CoV-2 structure with different herbal compounds of medicinal importance. We selected four <a>viral key proteins of SARS-CoV-2 </a>structure i.e ACE-2 Receptor, Main Protease (Mpro), APO Form, Cryo- electron microscopy structure for the Molecular docking followed by the molecular dynamic simulation. Using this simple in silico approach based on the molecular docking and <a>MD simulation </a>of protein and phytochemicals, we have identified potential lead candidates for the development of low cost nutraceuticals, which can be used against SARS-CoV-2 virus. Our analysis suggested that phytochemicals obtained from Phyllanthus emblica and Azadirachta indica have the highest potential to bind with ACE2 receptor or main protease of SARS-CoV-2, inhibiting the protease enzymatic activity. The lead compounds of herbal origin were docked and simulated on viral key proteins of SARS-CoV-2 structure to evaluate the binding affinity of these phytochemicals along with the type of interaction and its stability in terms of <a>RMSD</a> and <a>Ramachandran plot</a>. Further, these results were also verified by drug likeness properties by using SwissADME software. Overall, our results suggest that out of 14 herbal compounds, Nimbolide and Withaferin-A has great potential to be developed as low-cost nutraceuticals against SARS-CoV-2 virus, which is the need of hour.

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Dual modulators of selected plant secondary metabolites targeting COVID-19 Main protease and Interleukin-2: An in-silico approach based novel hypothesis

Coronaviruses ◽

10.2174/2666796701999200929124556 ◽

2020 ◽

Vol 01 ◽

Author(s):

Thangavelu Prabha ◽

Vijay K. Kapoor ◽

Palanisamy Selvamani ◽

Subbiah Latha ◽

Thangavel Sivakumar ◽

...

Keyword(s):

Immune Response ◽

Secondary Metabolites ◽

Binding Affinity ◽

In Silico ◽

Interleukin 2 ◽

Plant Secondary Metabolites ◽

Docking Study ◽

The Novel ◽

Standard Drug ◽

Main Protease

Background: Owing to the recent scenario on this ongoing Coronovirus pandemic outbreak around the world, the present study has been undertaken. Aim: In this study we adopted two strategies, i.e. via computational method;, a search for the novel plant secondary metabolites from the Indian Traditional Medicine to target and combat the enduring novel 2019 CoVs main protease that cause pneumonia, followed by the effect of these selected secondary metabolites on the host’s immune system for their immuno modulatory potential on Interleukin-2. Methods: A detailed literature review has been done, to identify the assorted plant secondary metabolites from the natural sources, which have been extensively used traditionally for their immuno modulatory potential. Next, the resulting compounds have processed for the molecular docking study to predict whether the compounds have the potency to fight against 2019- CoVs protein or it could have the tendency to battle the cytokines, which are responsible for the immune response of the host and there by prevent the CoVs caused infection in humans. Further, to explore molecular mechanics, the in-silico docking study with COVID-19 Mpro and Interleukin-2 has performed. Results & Discussion: Among the six secondary metabolites selected, five compounds showed its possible promising potency with COVID- 19 and IL-2 proteins, which are compared with the standard drug Remdesivir, an one of the anti-viral drug for treating and managing the present coronovirus condition and an IL-2 inhibitor which is the native IL-2 ligand protein (i.e. from PDB Id- 1PW6) itself. Besides, based on the docking scores the Curcumin (from Curcuma longa) showed the highest score towards these two targets taken for this study. The identified compounds have a promising binding affinity with the Mpro receptors, in the narrow range of binding energy for the protein PDB Id: 6LU7 and the score range has between -10.9102 to -19.8790 kcal/mol: when compared to the standard -21.8600 kcal/mol. Whereas, the binding affinity with Interleukin -2 receptor, for the protein PDB Id: 1PW6 the range between -11.3899 to -17.1366 kcal/mol: when compared to that of standard -16.9554 kcal/mol. Conclusion: Our results finding demonstrate that, the integrated Indian traditional herbal treatment might be hopefully used for the viral respiratory infection due to either it may have action directly on the viral protein or through regulating the immune response, which could lead to the rapid drug discovery of the drug leads with clinical potency towards the novel infectious disease, where there is no drug or vaccines are available.

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434.v1 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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