scholarly journals HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

2020 ◽  
Author(s):  
Marcelo Freitas Montenegro ◽  
Yousef Al-Abed ◽  
Mingzhu He ◽  
Kevin J. Tracey ◽  
Timothy R. Billiar
Keyword(s):  
Clinical Trials ◽  
Cathepsin L ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Potential Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a drug-based treatment for its control. Cathepsin L is an endosomal cysteine protease that mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells and viruses/host cell endosome membrane fusion. Therefore, cathepsin L is a potential target for the treatment of COVID-19 patients. In this report, we describe a previously unknown inhibitory effect of two FDA-approved drugs, saquinavir and nelfinavir, on human cathepsin L activity. Whether the pivotal role for cathepsin L in Sars-Cov-2 infection described in vitro can be translated to humans, our results support immediate clinical trials of saquinavir or nelfinavir as a potential treatment for COVID-19 patients.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

scholarly journals Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction

2020 ◽  
Author(s):  
ChangDong Lin ◽  
Yue Li ◽  
MengYa Yuan ◽  
MengWen Huang ◽  
Cui Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Inhibitory Concentration ◽  
Cell Entry ◽  
Host Cells ◽  
First Line ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.

scholarly journals Potential COVID-19 Protease Inhibitors: Repurposing FDAapproved Drugs

2020 ◽  
Author(s):  
Valentina Kouznetsova ◽  
David Huang ◽  
Igor F. Tsigelny
Keyword(s):  
Protease Inhibitors ◽  
Binding Pocket ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Free Energies ◽  
Inhibitor Binding ◽  
Approved Drugs ◽  
Docking Interaction ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Using as a template the crystal structure of COVID-19 protease, we developed a pharmacophore of functional centers of the protease inhibitor-binding pocket. Then we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of COVID-19 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.<br><br>

scholarly journals Molecular Docking and Molecular Dynamic Study of Two Viral Proteins Associated with SARS-CoV-2 with Ivermectin

2020 ◽  
Author(s):  
Lenin Andres Gonzalez Paz ◽  
Carla A. Lossada ◽  
Luis S. Moncayo ◽  
Freddy Romero ◽  
J. L. Paz ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Structural Changes ◽  
Inhibitory Effect ◽  
Parasitic Infections ◽  
Global Pandemic ◽  
Approved Drugs ◽  
3Cl Protease ◽  
Fda Approved Drugs

The global pandemic caused by the new SARS-COV-2 coronavirus makes it necessary to search for drugs for its control. Within of this research it has been known that the ivermectin drug, a FDA-approved drugs which is formulated as an 80:20 mixture of ivermectin B1a and B1b and used commonly for parasitic infections, has an inhibitory effect on viruses, includes SARS-COV-2 at in vitro level. In the particular case of SARS-COV-2 its mechanism of action remains elusive and controversial. Interestingly, the energy of interaction of ivermectin with any of the proteins the SARS-CoV-2 and the possible structural alterations at the protein level that this drug can cause have not been reported. In this sense, we carried out a bioinformatics study with docking strategies and molecular dynamics to predict the binding and disturbance induced by ivermectin in proteins associated with SARS-CoV-2. We use DockThor and Molegro docking scores. The DockThor server and myPresto software were used to build complexes and dynamics studies, respectively. The results obtained suggested that ivermectin is capable of docking with the 3CL protease and the HR2 domain, and may promote structural changes in these proteins by inducing unfolding/folding. Specifically, ivermectin brings protease to a significantly more deployed conformational state and the HR2 domain to a more compact state compared to the native state. Finally, it is shown that B1a and B1b macrocyclic lactones have a behavior different from to each target protein. These results suggest a possible inhibitory effect against SARS-CoV-2 due to a synergistic role of this drug to spontaneously bind to two important proteins involve in the proliferation of this virus. However, more studies are required on this possible mechanism of action.

Some FDA Approved drugs exhibit binding affinity as high as -16.0 kcal/mol against COVID-19 Main Protease (Mpro): A Molecular Docking Study

2020 ◽  
Author(s):  
Shanmuga Subramanian
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Antiviral Agent ◽  
Binding Energies ◽  
In Vitro Tests ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs

Currently the new Coronavirus "COVID-19", also known as SARS-CoV-2, has infected nearly 3 million patients and nearly 200,000+ people have lost their lives due to this pandemic. There is an urgent need to find an antiviral agent that may slow down the spread of the virus. The aim of this study is to assess and evaluate some FDA Approved drugs as potential inhibitors for COVID-19 Main Protease (Mpro) (PDB code: 6LU7). This will be done by blind molecular docking using PyRx and Auto Vina software. The compounds Hydroxychloroquine and Remdesivir were used for comparative study. The binding energies obtained from the docking of 6LU7 with Midostaurin, Zafirlukast, Eluxadoline, Naldemedine, Netupitant, Pancuronium, Letermovir, Baloxavir marboxil, Tazemetostat, Telotristat ethyl, Zeaxanthin, Lutein, Deserpidine, Cefotetan, Procaine benzylpenicillin were -16, 15.6, -15.3, -15.2, -15.1, -14.8, -14.6, -14.5, -13.8, -13.2, -13.2, -12.4, -12.4 and -11.2 kcal/mol respectively . Therefore some of the drugs can be used in Clinical trials as they are purified compounds of known composition and among all of them are approved drugs,some of them are investigative drugs except Pancuronium. All these drugs should be evaluated for further use by conducting in vitro tests and if they are successful they should evaluated for further use in clinical trials against COVID-19 as they are readily available in the market.

scholarly journals Potential COVID-19 Protease Inhibitors: Repurposing FDAapproved Drugs

2020 ◽  
Author(s):  
Valentina Kouznetsova ◽  
David Huang ◽  
Igor F. Tsigelny
Keyword(s):  
Protease Inhibitors ◽  
Binding Pocket ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Free Energies ◽  
Inhibitor Binding ◽  
Approved Drugs ◽  
Docking Interaction ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Using as a template the crystal structure of COVID-19 protease, we developed a pharmacophore of functional centers of the protease inhibitor-binding pocket. Then we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of COVID-19 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.<br><br>

scholarly journals Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3461
Author(s):  
Vasiliki Daikopoulou ◽  
Panagiotis Apostolou ◽  
Sofia Mourati ◽  
Ioanna Vlachou ◽  
Maria Gougousi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Drug Repositioning ◽  
Nucleoside Analogues ◽  
In Vitro Assays ◽  
Rna Dependent Rna Polymerase ◽  
Sugar Moiety ◽  
The Family ◽  
Approved Drugs ◽  
Fda Approved Drugs

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.

scholarly journals Current Potential Therapeutic Approaches against SARS-CoV-2: A Review

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1620
Author(s):  
Dharmendra Kumar Yadav ◽  
Desh Deepak Singh ◽  
Ihn Han ◽  
Yogesh Kumar ◽  
Eun-Ha Choi
Keyword(s):  
Wide Spectrum ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Therapeutic Approaches ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Nucleotide Analogue ◽  
Infection Treatment ◽  
Current Potential

The ongoing SARS-CoV-2 pandemic is a serious threat to public health worldwide and, to date, no effective treatment is available. Thus, we herein review the pharmaceutical approaches to SARS-CoV-2 infection treatment. Numerous candidate medicines that can prevent SARS-CoV-2 infection and replication have been proposed. These medicines include inhibitors of serine protease TMPRSS2 and angiotensin converting enzyme 2 (ACE2). The S protein of SARS-CoV-2 binds to the receptor in host cells. ACE2 inhibitors block TMPRSS2 and S protein priming, thus preventing SARS-CoV-2 entry to host cells. Moreover, antiviral medicines (including the nucleotide analogue remdesivir, the HIV protease inhibitors lopinavir and ritonavir, and wide-spectrum antiviral antibiotics arbidol and favipiravir) have been shown to reduce the dissemination of SARS-CoV-2 as well as morbidity and mortality associated with COVID-19.

scholarly journals Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

2018 ◽  
Author(s):  
R. N. V. Krishna Deepak ◽  
Ahmad Abdullah ◽  
Priti Talwar ◽  
Hao Fan ◽  
Palaniyandi Ravanan
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Specific Activity ◽  
Special Importance ◽  
Allosteric Inhibitors ◽  
Dimerization Interface ◽  
Executioner Caspases ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractThe regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

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