scholarly journals Target-Based Drug Discovery, ADMET Profiling and Bioactivity Studies of Antibiotics as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

2021 ◽  
Author(s):  
Misbaudeen Abdul-Hammed ◽  
Ibrahim Olaide Adedotun ◽  
Victoria Adeola Falade ◽  
Adewusi John Adepoju ◽  
Sabitu Babatunde Olasupo ◽  
...  
Keyword(s):  
Viral Infections ◽  
Binding Affinities ◽  
Computer Aided Drug Design ◽  
Online Tool ◽  
Main Protease ◽  
Recent Outbreak ◽  
Fast Spreading ◽  
Inhibitory Strength ◽  
Potential Inhibitors ◽  
Old Drugs

Abstract A recent outbreak of a new strain of Coronavirus (SARS-CoV-2) has become a global health burden, which has resulted in deaths. No proven drug has been found to effectively cure this fast-spreading infection, hence the need to explore old drugs with the known profile in tackling this pandemic. Computer-aided drug design approach involving virtual screening was used to obtain the binding scores and inhibiting efficiencies of previously known antibiotics against SARS-CoV-2 main protease (Mpro). In silico pre-clinical studies which include Drug-likeness, Bioactivity, and ADMET profiling were done using Molinspiration online tool and ADMET SAR2 webserver respectively, and the results were compared with those of drugs currently involved in clinical trials in the ongoing pandemic. Although antibiotics have been speculated to be of no use in the treatment of viral infections, literature has emerged lately to reveal antiviral potential and immune-boosting ability of antibiotics. This study identified Tarivid and Ciprofloxacin with binding affinities of -8.3 and − 8.1 kcal/mol, respectively as significant inhibitors of SARS-CoV-2 (Mpro) with better pharmacokinetics, drug-likeness and oral bioavailabity, bioactivity properties, ADMET properties and inhibitory strength compared to Remdesivir (-7.6 kcal/mol) and Azithromycin (-6.3 kcal/mol). These observations will provide insight for further research (clinical trial) in the cure and management of COVID-19.

scholarly journals Quinoline and Quinazoline Alkaloids against COVID-19: An In Silico Multitarget Approach

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Esraa M. O. A. Ismail ◽  
Shaza W. Shantier ◽  
Mona S. Mohammed ◽  
Hassan H. Musa ◽  
Wadah Osman ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
The Novel ◽  
Socioeconomic Impacts ◽  
Health Crisis ◽  
Natural Sources ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Potential Inhibitors

The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

In Silico Discovery of Novel Inhibitors Against Main Protease (Mpro) of SARS-CoV-2 Using Pharmacophore and Molecular Docking Based Virtual Screening from ZINC Database

2020 ◽  
Author(s):  
Zeshan Haider ◽  
Muhammad Muneeb Subhani ◽  
Muhammad Ansar Farooq ◽  
Maryum Ishaq ◽  
Maryam Khalid ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Effective Vaccine ◽  
Ligand Complex ◽  
Online Tool ◽  
Public Health Emergencies ◽  
Main Protease ◽  
Zinc Database ◽  
Recent Outbreak ◽  
Selection Of

Recent outbreak of Coronavirus Disease 2019 (COVID-19) caused by a novel ‘SARS-CoV-2’ virus resulted public health emergencies across the world. An effective vaccine to cure this virus is not yet available, thus requires concerted efforts at various scales. In this study, we employed Computer Aided Drug Design (CADD) based approach to identify the drug-like compounds - inhibiting the replication of main protease (Mpro) of SARS-CoV-2. Our database search using online tool “ZINC pharmer” retrieved ~1500 compounds based on pharmacophore features. Lipinski’s rule was applied to further evaluate the drug-like compounds, followed by molecular docking-based screening, and the selection of screening ligand complex with Mpro based on S-score (higher than reference inhibitor) and root-mean-square deviation (RMSD) value (less than reference inhibitor) using Molecular Operating Environment (MOE) system. Resultantly, ~200 compounds were identified having strong interaction with Mpro of SARS-CoV-2. After evaluating their binding energy using the MOE LigX algorithm, three compounds (ZINC20291569, ZINC90403206, ZINC95480156) were identified that showed highest binding energy with Mpro of SARS-CoV-2 and strong inhibition effect than the reference inhibitor. It is suggested that these candidate “drug-like compounds” have greater potential to stop the replication of SARS-CoV-2, hence might lead to the cure of COVID-19.

scholarly journals Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-Like Protease Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4896
Author(s):  
Marjorie C. L. C. Freire ◽  
Gabriela D. Noske ◽  
Natália V. Bitencourt ◽  
Paulo R. S. Sanches ◽  
Norival A. Santos-Filho ◽  
...  
Keyword(s):  
Viral Infections ◽  
Binding Mode ◽  
Global Scale ◽  
New Drugs ◽  
Binding Affinities ◽  
Main Protease ◽  
Inhibitory Activities ◽  
Inhibition Potencies ◽  
Catalytic Cleft ◽  
Micromolar Range

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28–65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0–3.5 µM) and binding affinities (Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.

scholarly journals Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

2020 ◽  
Vol 8 (7) ◽  
pp. 970 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Ahmed O. El-Gendy ◽  
Yara I. Shamikh ◽  
Lassaad Belbahri ◽  
...  
Keyword(s):  
Natural Products ◽  
Protein Complexes ◽  
Binding Free Energy ◽  
Binding Affinities ◽  
Binding Modes ◽  
Drug Candidates ◽  
Main Protease ◽  
Potential Inhibitors ◽  
Microbial Natural Products

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.

scholarly journals In silico Investigation of Saponins and Tannins as Potential Inhibitors of SARS-CoV-2 main Protease (Mpro)

2020 ◽  
Author(s):  
Victoria Adeola Falade ◽  
Temitope Isaac Adelusi ◽  
Ibrahim Olaide Adedotun ◽  
Misbaudeen Abdul-Hammed ◽  
Teslim Alabi Lawal ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Health Sector ◽  
Drug Discovery Process ◽  
Alternative Source ◽  
Synthetic Drugs ◽  
Main Protease ◽  
Preliminary Study ◽  
Potential Inhibitors ◽  
Old Drugs ◽  
Better Than

Abstract It is no longer news that a novel strain of coronavirus named SARS-CoV-2 is ravaging the health sector worldwide, several attempts have been made to curtail this pandemic via repurposing of old drugs but at the present, available drugs are not adequately effective. Over the year, plant phytochemicals are increasingly becoming an alternative source of an antimicrobial agent with a novel mechanism of action and limited side effects compared to synthetic drugs. Isolated saponins and tannins were evaluated for antiviral activity against SARS-CoV-2 Mpro via Molecular Docking and it was observed that a handsome number of the phytochemicals had binding affinity much better than Remdesivir, Dexamethasone, and N3 inhibitor which were used as the standard in this study. Further Investigation of drug-likeness, ADMET profile, and bioactivity of these phytochemicals revealed that binding affinity alone is not enough in the drug discovery process and that 4 hit compounds were identified as potential inhibitors of SARS-CoV-2Mpro. This preliminary study furnishes Ellagic acid, Arjunic acid, Theasapogenol B, and Euscaphic acid as potential inhibitors of SARS-CoV-2 Mpro with better pharmacokinetics and bioavailability compared to Remdesivir which is currently used compassionately.

In Silico Discovery of Novel Inhibitors Against Main Protease (Mpro) of SARS-CoV-2 Using Pharmacophore and Molecular Docking Based Virtual Screening from ZINC Database

2020 ◽  
Author(s):  
Zeshan Haider ◽  
Muhammad Muneeb Subhani ◽  
Muhammad Ansar Farooq ◽  
Maryum Ishaq ◽  
Maryam Khalid ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Effective Vaccine ◽  
Ligand Complex ◽  
Online Tool ◽  
Public Health Emergencies ◽  
Main Protease ◽  
Zinc Database ◽  
Recent Outbreak ◽  
Selection Of

Recent outbreak of Coronavirus Disease 2019 (COVID-19) caused by a novel ‘SARS-CoV-2’ virus resulted public health emergencies across the world. An effective vaccine to cure this virus is not yet available, thus requires concerted efforts at various scales. In this study, we employed Computer Aided Drug Design (CADD) based approach to identify the drug-like compounds - inhibiting the replication of main protease (Mpro) of SARS-CoV-2. Our database search using online tool “ZINC pharmer” retrieved ~1500 compounds based on pharmacophore features. Lipinski’s rule was applied to further evaluate the drug-like compounds, followed by molecular docking-based screening, and the selection of screening ligand complex with Mpro based on S-score (higher than reference inhibitor) and root-mean-square deviation (RMSD) value (less than reference inhibitor) using Molecular Operating Environment (MOE) system. Resultantly, ~200 compounds were identified having strong interaction with Mpro of SARS-CoV-2. After evaluating their binding energy using the MOE LigX algorithm, three compounds (ZINC20291569, ZINC90403206, ZINC95480156) were identified that showed highest binding energy with Mpro of SARS-CoV-2 and strong inhibition effect than the reference inhibitor. It is suggested that these candidate “drug-like compounds” have greater potential to stop the replication of SARS-CoV-2, hence might lead to the cure of COVID-19.

scholarly journals An in-silico evaluation of COVID-19 main protease with clinically approved drugs

2020 ◽  
Author(s):  
TACHOUA Wafa ◽  
KABRINE Mohamed ◽  
Mamona Mushtaq ◽  
Zaheer Ul-Haq
Keyword(s):  
Conformational Dynamics ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Wuhan City ◽  
Main Protease ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Binding Substrate

<p></p><p>A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M<sup>pro</sup> with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M<sup>pro </sup>crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL<sup>pro</sup>) of SARS-CoV-2. </p><br><p></p>

scholarly journals An in-silico evaluation of COVID-19 main protease with clinically approved drugs

2020 ◽  
Author(s):  
TACHOUA Wafa ◽  
KABRINE Mohamed ◽  
Mamona Mushtaq ◽  
Zaheer Ul-Haq
Keyword(s):  
Conformational Dynamics ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Wuhan City ◽  
Main Protease ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Binding Substrate

<p></p><p>A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M<sup>pro</sup> with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M<sup>pro </sup>crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL<sup>pro</sup>) of SARS-CoV-2. </p><br><p></p>

Identification of Main Protease of Coronavirus SARS-CoV-2 (Mpro)Inhibitors from Melissa officinalis

2020 ◽  
Vol 17 ◽  
Author(s):  
Olusola O. Elekofehinti ◽  
Opeyemi Iwaloye ◽  
Courage D. Famusiwa ◽  
Olanrewaju Akinseye ◽  
Joao B. T. Rocha
Keyword(s):  
Qsar Model ◽  
Computational Approach ◽  
Melissa Officinalis ◽  
Lead Compounds ◽  
Main Protease ◽  
The World ◽  
Recent Outbreak ◽  
Global Concern ◽  
Catalytic Dyad ◽  
Potential Therapeutic Intervention

Background: he recent outbreak of Coronavirus SARS-CoV-2 (Covid-19) which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. Compounds previously characterized from Melissa officinalis were queried against main protease of coronavirus SARS-CoV-2 using computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_28 (R2 = 0.8548 and Q2=0.6474, and was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as potential Mpro inhibitor.

scholarly journals Identification of Potential HCV Inhibitors Based on the Interaction of Epigallocatechin-3-Gallate with Viral Envelope Proteins

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1257
Author(s):  
Fareena Shahid ◽  
Noreen ◽  
Roshan Ali ◽  
Syed Lal Badshah ◽  
Syed Babar Jamal ◽  
...  
Keyword(s):  
Hepatitis C ◽  
In Silico ◽  
Experimental Validation ◽  
Homology Modelling ◽  
Viral Envelope ◽  
Screening Methods ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Potential Inhibitors ◽  
Very High

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.

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