Investigating Potential Inhibitory Effect of Uncaria tomentosa (Cat’s Claw) against the Main Protease 3CLpro of SARS-CoV-2 by Molecular Modeling

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CLpro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat’s claw), focusing on the inhibition of Mpro. The in silico approach starts with protein-ligand docking of 26 Cat’s claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat’s claw as complementary and/or alternative medicine for COVID-19 treatment.

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Investigating Potential Inhibitory Effect of Uncaria tomentosa (Cat's claw) against the Main Protease 3CLPro of SARS-CoV-2 by Molecular Modeling

10.20944/preprints202006.0326.v1 ◽

2020 ◽

Author(s):

Andres F. Yepes-Pérez ◽

Oscar Herrera-Calderon ◽

José-Emilio Sánchez-Aparicio ◽

Laura Tiessler-Sala ◽

Jean-Didier Maréchal ◽

...

Keyword(s):

In Silico ◽

Computational Study ◽

Inhibitory Effect ◽

Ligand Docking ◽

Therapeutic Effects ◽

Uncaria Tomentosa ◽

Main Protease ◽

Multi Level ◽

Dynamics Simulations ◽

Free Energy Of Binding

COVID-19 is a novel severe acute respiratory syndrome coronavirus. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CLpro) bound to a synthetic inhibitor which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat coronavirus disease 2019. It was carried out a multi-level computational study to evaluate the potential anti-viral properties of the components of the medicinal herb Uncaria tomentosa (Cat´s claw) focusing on the inhibition of Mpro. The in-silico approach starts with protein-ligand docking of 26 Cat’s claw key components followed by ligand pathway calculations, molecular dynamics simulations and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to the identification of three bioactive compounds of Uncaria tomentosa (Speciophylline, Cadambine and Proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and show good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment.

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

10.26434/chemrxiv.12281078 ◽

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>

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Computational Study on Novel Natural Inhibitors Targeting c-MET

10.21203/rs.3.rs-270054/v1 ◽

2021 ◽

Author(s):

Junliang Ge ◽

Bo Wu ◽

Wenzhuo Yang ◽

Sheng Zhong ◽

Yuanyuan Hou ◽

...

Keyword(s):

Molecular Dynamics ◽

Binding Affinity ◽

Computational Study ◽

Developmental Toxicity ◽

Inhibitory Effect ◽

Dynamics Simulation ◽

Drug Candidates ◽

Zinc Database ◽

The Stability ◽

Dynamics Simulations

Abstract Object This study was designed to select ideal lead compounds and preclinical drug candidates with inhibitory effect on c-MET from the drug library (ZINC database).Methods A battery of computer-aided virtual techniques were used to identify possible inhibitors of c-MET. LibDock is applied for structure-based screening followed by ADME (absorption, distribution, metabolic, excretion) and toxicity prediction. Molecular docking was conducted to confirm the binding affinity mechanism between the ligand and c-MET Molecular dynamics simulations were used to assess the stability of ligand-c-MET complexes.Results Two new natural compounds ZINC000005879645 and ZINC000002528509 were found to bind to c-MET in ZINC database, showing higher binding affinity. In addition, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000005879645 and ZINC000002528509 have more favorable potential energies with c-MET, which could exist stably in the natural environment.Conclusion This study suggests that ZINC000005879645 and ZINC000002528509 are ideal latent inhibitors of c-MET targeting. As drug candidates, these two compounds have great security and important implications for the design and improvement of c-MET target drugs.

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Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8830665 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Oscar Herrera-Calderon ◽

Andres F. Yepes-Pérez ◽

Jorge Quintero-Saumeth ◽

Juan Pedro Rojas-Armas ◽

Miriam Palomino-Pacheco ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Dynamic ◽

Cancer Progression ◽

In Silico ◽

Computational Study ◽

Female Rats ◽

Ligand Docking ◽

Dynamic Simulations ◽

In Silico Study ◽

Egfr Receptors

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

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In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database

Future Virology ◽

10.2217/fvl-2021-0099 ◽

2021 ◽

Author(s):

Eldar Muhtar ◽

Mengyang Wang ◽

Haimei Zhu

Keyword(s):

Molecular Dynamics ◽

Molecular Mechanics ◽

Protease Inhibitors ◽

Surface Area ◽

In Silico ◽

Binding Energies ◽

Main Protease ◽

Poisson Boltzmann ◽

Dynamics Simulations ◽

Potential Inhibitors

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

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In-vitro Cytotoxicity and Aromatase Inhibitory Activity of Flavonoids: Synthesis, Molecular Docking and In-silico ADME Prediction

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210827104406 ◽

2021 ◽

Vol 21 ◽

Author(s):

Umang Shah ◽

Samir Patel ◽

Mehul Patel ◽

Neeraj Jain ◽

Nilesh Pandey ◽

...

Keyword(s):

Breast Cancer ◽

Inhibitory Activity ◽

In Silico ◽

Computational Study ◽

Cancer Cell Line ◽

Inhibitory Effect ◽

In Vitro Cytotoxicity ◽

Spectroscopic Techniques ◽

Reference Drug

Background: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. Objective: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. Methods: 39 flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In-silico ADME properties were checked by QikPro software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. Results: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 μM, 1.636 μM, 16.08 μM, 22.02 μM, 15.75 μM, 0.345 μM and 16.08 μM, respectively, compared with the reference drug letrozole. The in-vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 μM and 0.36 μM, respectively. Conclusion: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 μM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

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In Silico Identification of Possible Inhibitors for Protein Kinase B (PknB) of Mycobacterium tuberculosis

Molecules ◽

10.3390/molecules26206162 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6162

Author(s):

Tatiana F. Vieira ◽

Fábio G. Martins ◽

Joel P. Moreira ◽

Tiago Barbosa ◽

Sérgio F. Sousa

Keyword(s):

Mycobacterium Tuberculosis ◽

Protein Kinases ◽

In Silico ◽

Structural Information ◽

Experimental Testing ◽

Binding Pocket ◽

Free Energy Calculations ◽

Ligand Docking ◽

Active Site Residues ◽

Dynamics Simulations

With tuberculosis still being one of leading causes of death in the world and the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), researchers have been seeking to find further therapeutic strategies or more specific molecular targets. PknB is one of the 11 Ser/Thr protein kinases of Mtb and is responsible for phosphorylation-mediated signaling, mainly involved in cell wall synthesis, cell division and metabolism. With the amount of structural information available and the great interest in protein kinases, PknB has become an attractive target for drug development. This work describes the optimization and application of an in silico computational protocol to find new PknB inhibitors. This multi-level computational approach combines protein–ligand docking, structure-based virtual screening, molecular dynamics simulations and free energy calculations. The optimized protocol was applied to screen a large dataset containing 129,650 molecules, obtained from the ZINC/FDA-Approved database, Mu.Ta.Lig Virtual Chemotheca and Chimiothèque Nationale. It was observed that the most promising compounds selected occupy the adenine-binding pocket in PknB, and the main interacting residues are Leu17, Val26, Tyr94 and Met155. Only one of the compounds was able to move the active site residues into an open conformation. It was also observed that the P-loop and magnesium position loops change according to the characteristics of the ligand. This protocol led to the identification of six compounds for further experimental testing while also providing additional structural information for the design of more specific and more effective derivatives.

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In silico molecular docking and molecular dynamics examination of Andrographis paniculata compounds of Andrographolide, Neoandrographolide, and 5-hydroxy-7,8,2’,3’-tetramethoxyflavone inhibition activity to SARS-CoV-2 main protease

BIO Web of Conferences ◽

10.1051/bioconf/20214107002 ◽

2021 ◽

Vol 41 ◽

pp. 07002

Author(s):

Raihan Kenji Rizqillah ◽

Jaka Fajar Fatriansyah ◽

Fadilah ◽

Sulhadi ◽

Siti Wahyuni ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

In Silico ◽

Andrographis Paniculata ◽

Dynamics Simulation ◽

Ligand Docking ◽

Inhibition Activity ◽

Docking Score ◽

Main Protease ◽

In Silico Molecular Docking

In this work, Andrographis paniculata compounds of Andrographolide, Neoandrographolide, and 5-hydroxy-7,8,2’,3’-tetramethoxyflavone inhibition activity to SARS CoV-2 main protease were examined through in silico molecular docking and molecular dynamics simulation, with Remdesivir as control ligand. Docking score and MMGBSA were examined as well as molecular dynamics parameters: RMSD, RMSF and Protein ligand contact fraction. Our study found that Andrographis paniculata compounds of Andrographolide, Neoandrographolide, and 5-hydroxy-7,8,2’,3’-tetramethoxyflavone have comparable inhibition activity to SARS CoV-2 main protease in comparison to Remdesivir. 5-hydroxy7,8,2’,3’-tetramethoxyflavone has the lowest docking score, which was further validated by protein ligand contact fraction examination, although MMGBSA score is lowest for Remdesivir.

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

10.26434/chemrxiv.12281078.v1 ◽

2020 ◽

Cited By ~ 2

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

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Medicinal Plants Against Coronavirus (SARS-COV-2) in Morocco Via Computational Virtual Screening Approach

10.21203/rs.3.rs-679827/v1 ◽

2021 ◽

Author(s):

Mohamed CHEBAIBI ◽

Dalila Bousta ◽

Rene Francisco Boschi Gonçalves ◽

Hasnae Hoummani ◽

Sanae Achour

Keyword(s):

Medicinal Plants ◽

Force Field ◽

Binding Affinity ◽

Inhibitory Effect ◽

Citrus Limon ◽

Organosulfur Compounds ◽

Syzygium Aromaticum ◽

Frequent Use ◽

Main Protease ◽

Dynamics Simulations

Abstract With the spread of the coronavirus in all countries of the world and in the absence of a vaccine or effective treatment to inhibit the infection. Several medicinal plants are used by the Moroccan population either to treat or prevent infection. The frequent use of its plants without documentation of their effectiveness on the Covid-19 is justified by cultural and economic reasons and their pharmacological activity scientifically proven. The objective of this study is to evaluate the inhibitory effect of the main polyphenols and flavonoids of Syzygium aromaticum and citrus limon as well as the main organosulfur compounds of garlic against coronavirus 6lu7 protease and 6y2e protease using in-silico molecular docking analysis.The COVID-19 3CLpro/Mpro (PDB ID: 6LU7) and free enzyme of the SARS-CoV-2 (2019- nCoV) main protease (PBD ID: 6Y2E) structures were obtained from the https://www.rcsb.org/ website in .PDB format. The COVID-19 3CLpro/Mpro (PDB ID: 6LU7) and main protease (PBD ID: 6Y2E) were prepared using autodock tools from MGL Tools package http://mgltools.scripps.edu/. The reactive molecular dynamics simulations were performed using the software LAMMPS and the ReaxFF force field. In this force field, the general energy functionWe have docked 34 natural products belonging to the three medicinal plants. In 6LU7 protease, 24 compounds exhibited a binding affinity greater than or equal to -6 Kcal/mol. While, in 6Y2E protease, 6 compounds exhibited a binding affinity greater than or equal to -6 Kcal/mol.We found that ellagic acid, narirutin, neoeriocitrin and neohesperidin are highly suggested as an inhibitor of SARS-COV-2.

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