scholarly journals Pharmacophore Analyses of SARS-CoV-2 Active Main Protease Inhibitors Using Pharmacophore Query and Docking Study

2020 ◽  
Author(s):  
Muhammet Karaman
Keyword(s):  
Hydrogen Bond ◽  
Aromatic Ring ◽  
Active Site ◽  
Pharmacophore Model ◽  
Docking Study ◽  
Cell Infection ◽  
Drug Candidates ◽  
Main Protease ◽  
Catalytic Active Site ◽  
Approved Drugs

The coronavirus disease (COVID-19) pandemic is the most important current problem in the world. Many researchers have focused on approved drugs or new drug candidates to combat the pandemic. Structural and nonstructural proteins of SARS-CoV-2 have been detected as targets for prevention of host cell infection or blockade of vital function. The main protease that plays an essential role in the virus life cycle is the optimal target. To design new inhibitors against the enzyme, the catalytic active site and substrate-binding site should be well analyzed. In this study, we generated a pharmacophore model using the cocrystallized pose of an active SARS-CoV-2 main protease inhibitor. According to the model, the inhibitor inhibits the enzyme via three hydrogen bond donors, two hydrogen bond acceptors and two aromatic ring interactions. Moreover, we docked reported active inhibitors of the main protease into the catalytic active site and detected matches between their pharmacophore models. The results showed that two close hydrogen acceptor/donor atom pairs and an aromatic ring are essential for enzyme inhibition.

scholarly journals Pharmacophore Analyses of SARS-CoV-2 Active Main Protease Inhibitors Using Pharmacophore Query and Docking Study

2020 ◽  
Author(s):  
Muhammet Karaman
Keyword(s):  
Hydrogen Bond ◽  
Aromatic Ring ◽  
Active Site ◽  
Pharmacophore Model ◽  
Docking Study ◽  
Cell Infection ◽  
Drug Candidates ◽  
Main Protease ◽  
Catalytic Active Site ◽  
Approved Drugs

The coronavirus disease (COVID-19) pandemic is the most important current problem in the world. Many researchers have focused on approved drugs or new drug candidates to combat the pandemic. Structural and nonstructural proteins of SARS-CoV-2 have been detected as targets for prevention of host cell infection or blockade of vital function. The main protease that plays an essential role in the virus life cycle is the optimal target. To design new inhibitors against the enzyme, the catalytic active site and substrate-binding site should be well analyzed. In this study, we generated a pharmacophore model using the cocrystallized pose of an active SARS-CoV-2 main protease inhibitor. According to the model, the inhibitor inhibits the enzyme via three hydrogen bond donors, two hydrogen bond acceptors and two aromatic ring interactions. Moreover, we docked reported active inhibitors of the main protease into the catalytic active site and detected matches between their pharmacophore models. The results showed that two close hydrogen acceptor/donor atom pairs and an aromatic ring are essential for enzyme inhibition.

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

scholarly journals Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

2020 ◽  
Author(s):  
Vijayakumar Balakrishnan ◽  
Karthik Lakshminarayanan
Keyword(s):  
Vaccine Development ◽  
New Drugs ◽  
World Health ◽  
Wuhan City ◽  
Drug Candidates ◽  
Human Contact ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger&rsquo;s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

scholarly journals Azadirachtin-A a bioactive compound from Azadiracta indica is a potential inhibitor of SARS-CoV-2 main protease

2021 ◽  
Vol 01 (01) ◽  
pp. 01-08
Author(s):  
Eustace Berinyuy ◽  
◽  
Jonathan Ibrahim ◽  
Blessing Alozieuwa
Keyword(s):  
Bioactive Compound ◽  
Docking Study ◽  
Preclinical Study ◽  
Binding Modes ◽  
Molecular Docking Study ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Binding Cavity ◽  
Approved Drugs ◽  
Azadirachtin A

Despite the growing scientific interest in finding effective treatment, SARS-CoV-2 virus remains a global major health burden and public health emergency. SARS-CoV main protease (Mpro) also known as chymotrypsin-like protease (3CLpro) is an important protein identified to be vital for SARS-CoV-2 survival. However, to date, there are no clinically approved drugs or antibodies specific for SARS-CoV-2. In the present study, we evaluated the interaction of 3CLpro with azadirachtin-A a bioactive compound from Azadiracta indica using in silico molecular docking study. Our results revealed that Azadiractin A docked well into the binding cavity of 3CLproSARS-CoV-2 with binding affinities ranges between -6.3 and -5.20 kcal/mol, and Pkd of 5.82~6.10 for the ten best binding modes. Azadiractin interacted with the active site of 3CLpro-SARS-CoV-2 by 2 conventional hydrogen bonding to HIS163 and GLU166, C-H interactions with HIS127, and alkyl interaction with PRO168 of the 3CLpro-SARS-CoV-2. We also found that the Azadiractin-A_3CLpro-SARS-CoV-2 complex is stabilized by various Vander wall forces with ASN142, LEU141, PHE140, MET165, GLN189, LEU167, THR190, and ALA191. In conclusion, our results suggested that Azadirachtin-A could be a potential inhibitor of SARS-CoV-2 main protease, thus worthy of further preclinical study.

The crystal structure of Proteus vulgaris tryptophan indole-lyase complexed with oxindolyl-L-alanine: implications for the reaction mechanism

2018 ◽  
Vol 74 (8) ◽  
pp. 748-759
Author(s):  
Robert S. Phillips ◽  
Adriaan A. Buisman ◽  
Sarah Choi ◽  
Anusha Hussaini ◽  
Zachary A. Wood
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bond ◽  
Aromatic Ring ◽  
Active Site ◽  
Enzymatic Reaction ◽  
Proteus Vulgaris ◽  
Bacterial Enzyme ◽  
Small Domain ◽  
Out Of Plane ◽  
Reversible Formation

Tryptophan indole-lyase (TIL) is a bacterial enzyme which catalyzes the reversible formation of indole and ammonium pyruvate from L-tryptophan. Oxindolyl-L-alanine (OIA) is an inhibitor of TIL, with a K i value of about 5 µM. The crystal structure of the complex of Proteus vulgaris TIL with OIA has now been determined at 2.1 Å resolution. The ligand forms a closed quinonoid complex with the pyridoxal 5′-phosphate (PLP) cofactor. The small domain rotates about 10° to close the active site, bringing His458 into position to donate a hydrogen bond to Asp133, which also accepts a hydrogen bond from the heterocyclic NH of the inhibitor. This brings Phe37 and Phe459 into van der Waals contact with the aromatic ring of OIA. Mutation of the homologous Phe464 in Escherichia coli TIL to Ala results in a 500-fold decrease in k cat/K m for L-tryptophan, with less effect on the reaction of other nonphysiological β-elimination substrates. Stopped-flow kinetic experiments of F464A TIL show that the mutation has no effect on the formation of quinonoid intermediates. An aminoacrylate intermediate is observed in the reaction of F464A TIL with S-ethyl-L-cysteine and benzimidazole. A model of the L-tryptophan quinonoid complex with PLP in the active site of P. vulgaris TIL shows that there would be a severe clash of Phe459 (∼1.5 Å apart) and Phe37 (∼2 Å apart) with the benzene ring of the substrate. It is proposed that this creates distortion of the substrate aromatic ring out of plane and moves the substrate upwards on the reaction coordinate towards the transition state, thus reducing the activation energy and accelerating the enzymatic reaction.

scholarly journals Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study.

2020 ◽  
Author(s):  
Salim Bouchentouf ◽  
Noureddine Missoum
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Nigella Sativa ◽  
Specific Treatment ◽  
Docking Study ◽  
Clinical Test ◽  
Molecular Docking Study ◽  
Great Opportunity ◽  
Drug Candidates ◽  
Energy Score

<p>The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new probable inhibitors of COVID-19 by molecules from <i>Nigella sativa L</i>, which is highly reputed healing herb in North African societies and both Islamic and Christian traditions. The discovery of the M<sup>pro</sup> protease structure in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the main proteases in CoVs (3CL<sup>pro</sup>/M<sup>pro</sup>) (PDB ID 6LU7 and 2GTB); docking of compounds from <i>Nigella Sativa</i> and drugs under clinical test was performed using Molecular Operating Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir (-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive use of <i>Nigella Sativa </i>against coronavirus infection.</p>

scholarly journals MOLECULAR DOCKING STUDY TO IDENTIFY POTENTIAL INHIBITOR OF COVID-19 MAIN PROTEASE ENZYME: AN IN-SILICO APPROACH

2020 ◽  
Author(s):  
Anurag Agrawal ◽  
Nem Kumar Jain ◽  
Neeraj Kumar ◽  
Giriraj T Kulkarni
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Potential Threat ◽  
Discovery Studio ◽  
Chemical Structures ◽  
Potential Inhibitor ◽  
Protease Enzyme ◽  
Main Protease

This study belongs to identification of suitable COVID-19 inhibitors<br><div><br></div><div>Coronavirus became pandemic very soon and is a potential threat to human lives across the globe. No approved drug is currently available therefore an urgent need has been developed for any antiviral therapy for COVID-19. For the molecular docking study, ten herbal molecules have been included in the current study. The three-dimensional chemical structures of molecules were prepared through ChemSketch 2015 freeware. Molecular docking study was performed using AutoDock 4.2 simulator and Discovery studio 4.5 was employed to predict the active site of target enzyme. Result indicated that all-natural molecules found in the active site of enzyme after molecular docking. Oxyacanthine and Hypericin (-10.990 and -9.05 and kcal/mol respectively) have shown good binding efficacy among others but Oxyacanthine was the only natural product which made some of necessary interactions with residues in the enzyme require for target inhibition. Therefore Oxyacanthine may be considered to be potential inhibitor of main protease enzyme of virus but need to be explored for further drug development process. <br></div>

scholarly journals Molecular Docking and Molecular Dynamics Studies of SARS-CoV-2 Inhibitors: Crocin, Digitoxigenin, Beta-Eudesmol and Favipiravir: Comparative Study

2021 ◽  
Vol 12 (4) ◽  
pp. 5591-5600
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Comparative Study ◽  
Active Site ◽  
Antiviral Treatment ◽  
Docking Study ◽  
The Other ◽  
Dynamics Simulation ◽  
Main Protease

In this study, Crocin, Digitoxigenin, Beta-Eudesmol, and Favipiravir were docked in the active site of SARS-CoV-2 main protease (PDB code: 6LU7). The docking study was followed by Molecular Dynamics simulation. The result indicates that Crocin and Digitoxigenin are the structures with the best affinity in the studied enzyme's binding site. Still, Molecular Dynamics simulation showed that Digitoxigenin is the molecule that fits better in the active site of the main protease. Therefore, this molecule could have a more potent antiviral treatment of COVID-19 than the other three studied compounds.

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

2021 ◽  
Vol 71 (2) ◽  
pp. 163-174
Author(s):  
Safa Daoud ◽  
Shada J. Alabed ◽  
Lina A. Dahabiyeh
Keyword(s):  
Binding Site ◽  
Protease Inhibitors ◽  
Specific Binding ◽  
Antiviral Drug ◽  
Pharmacophore Model ◽  
Docking Study ◽  
Pharmacophore Modeling ◽  
Antiviral Drugs ◽  
Crystallographic Structure ◽  
Main Protease

AbstractThe 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.

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