scholarly journals Natural Compounds Activities against SARS-CoV-2 Mpro through Bioinformatics Approaches for Development of Antivirus Candidates

2021 ◽  
Vol 24 (5) ◽  
pp. 170-176
Author(s):  
Taufik Muhammad Fakih
Keyword(s):  
Binding Free Energy ◽  
Natural Compounds ◽  
Protein Docking ◽  
Ligand Docking ◽  
Angiotensin Converting Enzyme 2 ◽  
Docking Simulations ◽  
Main Protease ◽  
Alternative Approach ◽  
Therapeutic Mechanism ◽  
Almost All

Coronavirus infection (COVID-19) caused by SARS-CoV-2 appears as a pandemic that has spread to almost all countries in the world. Antiviral therapy using natural compounds is one alternative approach to overcome this infectious disease. The therapeutic mechanism is proven effective against the main protease (Mpro) of SARS-CoV-2. This research aims to perform bioinformatics studies, including ligand-docking simulations and protein-protein docking simulations, to identify, evaluate, and explore five compounds' activity on SARS-CoV-2 Mpro and their effects against Angiotensin-Converting Enzyme 2 (ACE-2). Protein-ligand docking simulations show kaempferol, flavonol, and their glycosides (Afzelin and Juglanin) and other flavonoids (Quercetin, Naringenin, and Genistein) have a high affinity towards SARS-CoV-2 Mpro. These results were then confirmed using protein-protein docking simulations to observe the ability of five compounds to prevent the attachment of ACE-2 to the active site. Based on the results of the bioinformatics studies, Quercetin has the best affinity, with a binding free energy value of −33.18 kJ/mol. The five compounds are predicted to be able to interact strongly with SARS-CoV-2. The results in this research are useful for further studies in the development of novel anti-infective drugs for COVID-19 that target SARS-CoV-2 Mpro.

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals In silico Screening of Natural Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike RBD: Targets for COVID-19

2021 ◽  
Vol 7 ◽  
Author(s):  
Divya M. Teli ◽  
Mamta B. Shah ◽  
Mahesh T. Chhabria
Keyword(s):  
Binding Free Energy ◽  
Treatment Options ◽  
Natural Compounds ◽  
Pharmacokinetic Parameters ◽  
Main Protease ◽  
Glide Docking ◽  
Docking Approach ◽  
Covalent Docking ◽  
Dual Inhibitors ◽  
Potential Inhibitors

Historically, plants have been sought after as bio-factories for the production of diverse chemical compounds that offer a multitude of possibilities to cure diseases. To combat the current pandemic coronavirus disease 2019 (COVID-19), plant-based natural compounds are explored for their potential to inhibit the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The present study is aimed at the investigation of antiviral action of several groups of phytoconstituents against SARS-CoV-2 using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to ACE2 (PDB code: 6M0J) of SARS-CoV-2. For binding affinity evaluation, the docking scores were calculated using the Extra Precision (XP) protocol of the Glide docking module of Maestro. CovDock was also used to investigate covalent docking. The OPLS3e force field was used in simulations. The docking score was calculated by preferring the conformation of the ligand that has the lowest binding free energy (best pose). The results are indicative of better potential of solanine, acetoside, and rutin, as Mpro and spike glycoprotein RBD dual inhibitors. Acetoside and curcumin were found to inhibit Mpro covalently. Curcumin also possessed all the physicochemical and pharmacokinetic parameters in the range. Thus, phytochemicals like solanine, acetoside, rutin, and curcumin hold potential to be developed as treatment options against COVID-19.

Protein-ligand Docking Simulations with AutoDock4 Focused on the Main Protease of SARS-CoV-2

2021 ◽  
Vol 28 ◽  
Author(s):  
Walter Filgueira de Azevedo Junior ◽  
Gabriela Bitencourt-Ferreira ◽  
Joana Retzke Godoy ◽  
Hilda Mayela Aran Adriano ◽  
Wallyson André dos Santos Bezerra ◽  
...  
Keyword(s):  
Scientific Evidence ◽  
Three Dimensional ◽  
Structural Data ◽  
Ligand Docking ◽  
Dimensional Structure ◽  
Computational Approaches ◽  
Docking Simulations ◽  
Protein Target ◽  
Main Protease ◽  
Docking Protocol

Background: The main protease of SARS-CoV-2 (Mpro) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies. Objective: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the Mpro using the program AutoDock4. Method: We searched PubMed to identify studies that applied AutoDock4 for docking against this protein target. We used the structures available for Mpro to analyze intermolecular interactions and reviewed the methods used to search for inhibitors. Results: The application of docking against the structures available for the Mpro found ligands with an estimated inhibition in the nanomolar range. Such computational approaches focused on the crystal structures revealed potential inhibitors of Mpro that might exhibit pharmacological activity against SARS-CoV-2. Nevertheless, most of these studies lack the proper validation of the docking protocol. Also, they all ignored the potential use of machine learning to predict affinity. Conclusion: The combination of structural data with computational approaches opened the possibility to accelerate the search for drugs to treat COVID-19. Several studies used AutoDock4 to search for inhibitors of Mpro. Most of them did not employ a validated docking protocol, which lends support to critics of their computational methodology. Furthermore, one of these studies reported the binding of chloroquine and hydroxychloroquine to Mpro. This study ignores the scientific evidence against the use of these antimalarial drugs to treat COVID-19.

scholarly journals Discovery of New Delhi Metallo-β-Lactamase-1(NDM-1) Inhibitors From Natural Compounds: In Silico-Based Methods

2020 ◽  
Author(s):  
Azhar Salari-jazi ◽  
Karim Mahnam ◽  
Parisa Sadeghi ◽  
Mohammad Sadegh Damavandi ◽  
Jamshid Faghri
Keyword(s):  
Binding Free Energy ◽  
Experimental Studies ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Health Concern ◽  
Multi Drug Resistance ◽  
New Delhi ◽  
Public Health Concern ◽  
Different Types ◽  
Almost All

Abstract New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for new Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with new Delhi metallo-β-lactamase. 3D conformational alignment and protein sequence alignment of all new Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Then the conserved and crucial residues in the catalytic activity of metallo-β-lactamases were detected. These residues had similar 3D coordinates in the 3D conformational alignment. So it is possible that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all new Delhi metallo-β-lactamase and metallo-β-lactamases in experimental studies.

scholarly journals Identification of the Potential Hits for Hindering Interaction of SARS-CoV-2 Main Protease (M pro ) from the Pool of Antiviral Phytochemicals utilizing Molecular Docking and Molecular Dynamics (MD) Simulations

2021 ◽  
Author(s):  
Chirag N. Patel ◽  
Dharmesh G. Jaiswal ◽  
Siddhi P. Jani ◽  
Naman Mangukia ◽  
Robin M. Parmar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Virus Assembly ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Host Protein ◽  
Dynamic Simulations ◽  
Main Protease

Abstract The novel SARS-CoV-2 is an etiological factor that triggers Coronavirus disease in 2019 (COVID-19) and tends to be an imminent occurrence of a pandemic. Out of all recognized solved complexes linked to SARS-CoV, Main protease (Mpro) is considered a desirable antiviral phytochemical that play a crucial role in virus assembly and possibly non-interactive capacity to adhere to any viral host protein. In this research, SARS-CoV-2 MPro was chosen as a focus for the detection of possible inhibitors using a variety of different analytical methods such as molecular docking, ADMET analysis, dynamic simulations and binding free energy measurements. Virtual screening of known natural compounds recognized Withanoside V, Withanoside VI, Racemoside B, Racemoside A and Shatavarin IX as future inhibitors of SARS-CoV-2 MPro with stronger energy binding. Also, simulations of molecular dynamics for a 100 ns time scale showed that much of the main SARS-CoV-2 MPro interactions had been maintained in the simulation routes. Binding free energy calculations using the MM/PBSA method ranked the top five possible natural compounds that can act as effective SARS-CoV-2 MPro inhibitors.

scholarly journals Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chirag N. Patel ◽  
Siddhi P. Jani ◽  
Dharmesh G. Jaiswal ◽  
Sivakumar Prasanth Kumar ◽  
Naman Mangukia ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Public Health Care ◽  
Dynamic Simulations ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

AbstractNovel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

2020 ◽  
Author(s):  
Md Tabish Rehman ◽  
Mohamed F AlAjmi ◽  
Afzal Hussain
Keyword(s):  
Hydrophobic Interactions ◽  
Rapid Development ◽  
Economic Loss ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Active Site Residues ◽  
Reference Drug ◽  
Drug Molecules ◽  
Main Protease ◽  
Alternative Approach

<p>Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and costly in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (M<sup>pro</sup> or 3CL<sup>pro</sup>) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CL<sup>pro</sup> with high affinity (10<sup>5</sup>-10<sup>6</sup> M<sup>-1</sup>) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest the potential of natural compounds (flavonoids) as novel inhibitors of SARS-CoV-2 with comparable potency as that of Remdesivir.</p>

Potential Inhibitors Identification of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Angiotensin-Converting Enzyme 2 and Main Protease from Anatolian Traditional Plants

2021 ◽  
Vol 19 ◽  
Author(s):  
Namık Kılınç ◽  
Mikail Açar ◽  
Salih Tuncay ◽  
Ömer Faruk Karasakal
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Chlorogenic Acid ◽  
Caffeic Acid ◽  
Rosmarinic Acid ◽  
Carnosic Acid ◽  
Binding Affinities ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Docking Simulations ◽  
Main Protease

Background: The 2019 novel coronavirus disease (COVID-19) has caused a global health catastrophe by affecting the whole human population around the globe. Unfortunately, there is no specific medication or treatment for COVID-19 currently available. Objective: It’s extremely necessary to apply effective drug treatment in order to end the pandemic period and return daily life to normal. In terms of the urgency of treatment, rather than focusing on the discovery of novel compounds, it is critical to explore the effects of existing herbal agents with proven antiviral properties on the virus. Method: Molecular docking studies were carried out with three different methods, Glide extra precision (XP) docking, Induced Fit docking (IFD), and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), to determine the potential effects of 58 phytochemicals in the content of Rosmarinus officinalis, Thymbra spicata, Satureja thymbra, and Stachys lavandulifolia plants -have antiviral and antibacterial effects- against Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) enzymes. Results: 7 compounds stand out among all molecules by showing very high binding affinities. According to our findings, the substances chlorogenic acid, rosmarinic acid, and rosmanol exhibit extremely significant binding affinities for both Mpro and ACE2 enzymes. Furthermore, it was discovered that carnosic acid and alpha-cadinol showed potential anti-Mpro activity, whereas caffeic acid and carvacrol had promising anti-ACE2 activity. Conclusion: Chlorogenic acid, rosmarinic acid, rosmanol, carnosic acid, alpha-cadinol, caffeic acid, and carvacrol compounds have been shown to be powerful anti-SARS-COV-2 agents in docking simulations against Mpro and ACE2 enzymes, as well as ADME investigations.

scholarly journals Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

2020 ◽  
Author(s):  
Suryakant Tiwari ◽  
Raghav Jain ◽  
Indrani Banerjee
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Active Site ◽  
Ligand Docking ◽  
Kcal Mole ◽  
Main Protease ◽  
Alternative Approach ◽  
Repurposed Drugs ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV-2 is one of the greatest pandemics in the history. There is no medicine or vaccine yet discovered to control the outbreak. The paper deals with repurposing existing drugs to control the outbreak of SARS-CoV-2 virus.Ten FDA-approved drugs namely Indinavir, Nelfinavir, Letermovir, Irinotecan, Elbasvir, Saquinavir, Darunavir, Raltegravir, Atazanavir and Amprenavir were studied. In silico methods for virtual screening of protein-ligand docking of these drugs against SARS-CoV-2 MPro was performed. The binding efficiency of the drugs against viral main protease MPro was significantly high to inhibit SARS-CoV-2.The results confirmed that Atazanavir, Nelfinavir, and Letermovir not only occupied the active site of Mpro but also showed increased binding affinity (-10.36 kcal/mole, -9.47 kcal/mole and -9.43 kcal/mole) even more than of control drugs of Lopinavir (-8.71 kcal/mole) and Ritonavir (-8.08 kcal/mole). These repurposed drugs can be used in combination or individually as an alternative approach for rapid drug discovery against SARS-CoV-2

Sign in / Sign up

Export Citation Format

Share Document