scholarly journals In silico drug repurposing of anticancer drug 5-FU and analogues against SARS-CoV-2 main protease

2021 ◽  
Author(s):  
Aristote Matondo ◽  
Washington Dendera ◽  
Bienfait K. Isamura ◽  
Koto-te-Nyiwa Ngbolua ◽  
Hilaire V.S. Mambo ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Pharmacological Action ◽  
Time Saving ◽  
Therapeutic Uses ◽  
Main Protease ◽  
Approved Drugs ◽  
Effective Drugs ◽  
Therapeutic Profile

The pressing need to find effective drugs against the current deadly COVID-19 disease has recently motivated numerous studies using different approaches to address the problem. One time-saving and less costly strategy is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same trend, this study has investigated the potential inhibitory activity of 5-FU and its analogues against the SARS-CoV-2 main protease as well as their profile of druggability using molecular docking and ADMET methods. From the calculations performed, four candidates showed promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. Further in-vitro and in-vivo investigations are needed that may clarify their possible mechanism of the pharmacological action to combat COVID-19.

scholarly journals Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Carlos Javier Alméciga-Díaz ◽  
Luisa N. Pimentel-Vera ◽  
Angela Caro ◽  
Angela Mosquera ◽  
Camilo Andrés Castellanos Moreno ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Clinical Information ◽  
Virus Genome ◽  
Pharmacological Agents ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals Sulfisoxazole does not inhibit the secretion of small extracellular vesicles

2020 ◽  
Author(s):  
Pamali Fonseka ◽  
Sai V Chitti ◽  
Rahul Sanwlani ◽  
Suresh Mathivanan
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Drug Repurposing ◽  
Tumor Burden ◽  
Immunocompetent Mouse ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractRecently, the study by Im et al. focused on blocking the release of extracellular vesicles (EVs) by cancer cells, as a strategy to block metastasis, by deploying a drug repurposing screen. Upon screening the library of FDA approved drugs in breast cancer cells in vitro, the authors reported the ability of the antibiotic Sulfisoxazole (SFX) in inhibiting EV biogenesis and secretion. SFX was also effective in reducing breast primary tumor burden and blocking metastasis in immunocompromised and immunocompetent mouse models. As we seek a compound to block EV biogenesis and secretion in our current in vivo studies, we intended to use SFX and hence performed in vitro characterization as the first step. However, treatment of two cancer cells with SFX did not reduce the amount of EVs as reported by the authors.

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 COVID19 Approved Drug Repurposing: Pocket Similarity Approach

2020 ◽  
Author(s):  
Mohamed Fadlalla
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Drug Binding Site ◽  
Main Protease ◽  
Major Outbreak ◽  
Target Binding ◽  
Approved Drugs

<p>SARS CoV 2 has spread worldwide and caused a major outbreak of coronavirus disease 2019 (COVID-19). To date, no licensed drug or a vaccine is available against COVID19.</p><p>Starting from all of the resolved SARS CoV2 crystal structures, this study aims to find inhibitors for all of the SARS CoV2 proteins. To achieve this, I used PocketMatch to test the similarity of approved drugs binding sites against all of the binding sites found on SARS CoV 2 proteins. After that docking was used to confirm the results.</p><p>I found drugs that inhibit the main protease, Nsp12 and Nsp3. The discovered drugs are either in clinical trials (Sildenafil, Lopinavir, Ritonavir) or have in vitro antiviral activity (Nelfinavir, Indinavir, Amprenavir, depiqulinum , Gemcitabine, Raltitrexed, Aprepitant, montelukast, Ouabain, Raloxifene) whether against SARS CoV 2 or other viruses. In addition to this, further analysis of pockets revealed a steroidal pocket that might open the door to hypotheses on why the mortality of men is higher than women.</p><p>Many of the in silico repurposing studies test binding of the compound to the target using docking. The significance of this study adds to the similarity between the drug binding site and the target binding site. This takes into consideration the dynamic behaviour of the pocket after ligand binding.</p><div><br></div>

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals Repurposing inhibitors for SARS-CoV2 main protease

2020 ◽  
Author(s):  
Kumar Sharp
Keyword(s):  
Viral Replication ◽  
Active Sites ◽  
Drug Repurposing ◽  
Chemotherapeutic Drugs ◽  
Short Term ◽  
Main Protease ◽  
Potential Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising field to provide potential short-term acceptable therapy for management of coronavirus till a specific anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish final fact.

scholarly journals Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

2020 ◽  
Author(s):  
Stuart Weston ◽  
Christopher M. Coleman ◽  
Rob Haupt ◽  
James Logue ◽  
Krystal Matthews ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Ic50 Values ◽  
Human Use ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractSARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

scholarly journals Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

2020 ◽  
Author(s):  
Lovika Mittal ◽  
Anita Kumari ◽  
Mitul Srivastava ◽  
Mrityunjay Singh ◽  
Shailendra Asthana
Keyword(s):  
Virtual Screening ◽  
Design Method ◽  
Hot Spot ◽  
Drug Repurposing ◽  
Inhibitory Effect ◽  
Drug Molecules ◽  
Main Protease ◽  
Approved Drugs ◽  
Novel Drug

<p>In this work, computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19 main protease (M<sup>pro</sup>)<sup> </sup>. The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 M<sup>pro</sup> to identify potential drug molecules. With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVID-19 M<sup>pro</sup>. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8.0 kcal/mol and MMGBSA > -68.0 kcal/mol. The binding pattern of these compounds suggests that they interacted with key <i>hot-spot</i> residues. Also, their pharmacokinetic annotations and therapeutic importance have indicated that they possess drug-like properties and could pave their way for<i> in-vitro</i> studies. The findings of this work will be significant for structure and pharmacophore-based designing. </p>

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>

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