scholarly journals Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5501
Author(s):  
Teresa L. Augustin ◽  
Roxanna Hajbabaie ◽  
Matthew T. Harper ◽  
Taufiq Rahman
Keyword(s):  
In Silico ◽  
3D Structure ◽  
The Novel ◽  
Health Crisis ◽  
Protein Ligand Interactions ◽  
Main Protease ◽  
Ligand Interactions ◽  
Spanish Flu ◽  
Active Fragments ◽  
Novel Coronavirus

The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein–ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.

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.

scholarly journals In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

2020 ◽  
Author(s):  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Mohammed Ahmed ◽  
Deepsikha Kar ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Active Site ◽  
In Silico ◽  
3D Structure ◽  
Drug Repurposing ◽  
The Novel ◽  
Lead Compounds ◽  
Nucleotidyl Transferase ◽  
Domain Organisation ◽  
Novel Coronavirus ◽  
In Silico Characterization

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of the RdRp from the novel coronavirus – SARS-CoV2, provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, this study predicts that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds GTP and UTP at its proposed active site. Additionally, using molecular docking this study predicts the binding of five well characterized anti-microbial compounds at the NiRAN domain active site and their drug-likeliness and DFT properties. In line with the current global COVID-19 pandemic urgency, this study provides a new target and potential lead compounds for drug repurposing against SARS-CoV2.

scholarly journals The landscape of disinformation on health crisis communication during the COVID-19 pandemic in Ukraine: hybrid warfare tactics, fake media news and review of evidence

2020 ◽  
Vol 19 (05) ◽  
pp. A02
Author(s):  
Sonny Patel ◽  
Omar Moncayo ◽  
Kristina Conroy ◽  
Doug Jordan ◽  
Timothy Erickson
Keyword(s):  
Social Media ◽  
Crisis Communication ◽  
Scientific Literature ◽  
The Novel ◽  
Hybrid Warfare ◽  
Health Crisis ◽  
Medical Response ◽  
The World ◽  
Spanish Flu ◽  
Novel Coronavirus

The COVID-19 pandemic has impacted the world in ways not seen since the 1918–1920 Spanish Flu. Disinformation campaigns targeting health crisis communication during this pandemic seek to cripple the medical response to the novel coronavirus and instrumentalize the pandemic for political purposes. Propaganda from Russia and other factions is increasingly infiltrating public and social media in Ukraine. Still, scientific literature has only a limited amount of evidence of hybrid attacks and disinformation campaigns focusing on COVID-19 in Ukraine. We conducted a review to retrospectively examine reports of disinformation surrounding health crisis communication in Ukraine during the COVID-19 response. Based on the themes that emerged in the literature, our recommendations are twofold: 1) increase transparency with verified health crisis messaging and, 2) address the leadership gap in reliable regional information about COVID-19 resources and support in Ukraine.

scholarly journals In Silico Study of Curcumin and Folic Acid as Potent Inhibitors of Human Transmembrane Protease Serine 2 in the Treatment of COVID-19

2020 ◽  
pp. 3-9
Author(s):  
Noboru Motohashi ◽  
Anuradha Vanam ◽  
Rao Gollapudi
Keyword(s):  
Folic Acid ◽  
In Silico ◽  
3D Structure ◽  
Bond Energies ◽  
Protein Activity ◽  
Drug Candidates ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
In Silico Simulation ◽  
Surface Receptor

Background. Human transmembrane protease 2 (TMPRSS2) protein is essential for priming spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with human angiotensin-converting enzyme 2 (ACE2) surface receptor to facilitate viral invasion into host human cell through ACE2 receptor. Impeding TMPRSS2 protein activity is currently a preferred choice of the treatment of coronavirus disease 2019 (COVID-19) which is caused by SARS-CoV-2. Curcumin and folic acid are potential candidates for inhibiting TMPRSS2. Objective. The present study aimed to demonstrate the inhibitory activities of curcumin and folic acid, along with known human serine protease inhibitors such as nafamostat and camostat, on TMPRSS2. Methods. Curcumin and folic acid, along with nafamostat and camostat, were docked on a modeled human TMPRSS2 protein 3D structure. Nafamostat and curcumin interactions with targeted TMPRSS2 protein were identical whereas camostat and folic acid displayed similar interactions. Results. The hydrogen bond (H-bond) energies of docked curcumin, folic acid, nafamostat, and camostat were −19.86 kJ/mol, −17.63 kJ/mol, −10.53 kJ/mol, and −14.41 kJ/mol, respectively. Higher H-bond energies could strengthen protein-ligand interactions. Our results showed binding site similarities between curcumin and nafamostat as well as folic acid and camostat. Conclusion. The current in silico simulation suggested that curcumin and folic acid displayed binding poses with TMPRSS2 which are similar to nafamostat and camostat. Therefore, curcumin and folic acid could emerge as potential drug candidates to control COVID-19.

scholarly journals In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2529 ◽  
Author(s):  
Phaedra Eleftheriou ◽  
Dionysia Amanatidou ◽  
Anthi Petrou ◽  
Athina Geronikaki
Keyword(s):  
Protease Inhibitors ◽  
In Silico ◽  
Drug Targets ◽  
3D Structure ◽  
Coagulation Factor ◽  
Surface Protein ◽  
The Novel ◽  
Docking Analysis ◽  
Main Protease ◽  
Hcv Protease

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.

scholarly journals Deep Learning Based Drug Screening for Novel Coronavirus 2019-nCov

2020 ◽  
Author(s):  
Haiping Zhang ◽  
Konda Mani Saravanan ◽  
Yang Yang ◽  
Md. Tofazzal Hossain ◽  
Junxin Li ◽  
...  
Keyword(s):  
Deep Learning ◽  
Immune Responses ◽  
Drug Screening ◽  
Alternative Methods ◽  
Rna Sequences ◽  
Protein Ligand Interactions ◽  
Virus Rna ◽  
Main Protease ◽  
Ligand Interactions ◽  
Novel Coronavirus

A novel coronavirus called 2019-nCoV was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. 2019-nCoV spreads more rapidly than SARS-CoV. Unfortunately, there is no drug to combat the virus. It is of high significance to develop a drug that can combat the virus effectively before the situation gets worse. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In this paper, we first collected virus RNA sequences from the GISAID database, translated the RNA sequences into protein sequences, and built a protein 3D model using homology modeling. Coronavirus main protease is considered to be a major therapeutic target, thus this paper focused on drug screening based on the modeled 2019-nCov_main_protease structure. The deep learning based method DFCNN, developed by our group, can identify/rank the protein-ligand interactions with relatively high accuracy. DFCNN is capable of performing virtual screening quickly since no docking or molecular dynamic simulation is needed. DFCNN identifies potential drugs for 2019-nCoV protease by performing drug screening against 4 chemical compound databases. Also, we performed drug screening for all tripeptides against the binding site of 2019-nCov_main_protease since peptides often show better stability, more bio-availability and negligible immune responses. In the end, we provided the list of possible chemical ligands and peptide drugs for experimental validation.

scholarly journals In silico evaluation of isatin-based derivatives with RNA-dependent RNA polymerase of the novel coronavirus SARS-CoV-2

2020 ◽  
Author(s):  
Rajesh Kumar M ◽  
Daniel Andrew Gideon ◽  
Richard Mariadasse ◽  
Vijay Nirusimhan ◽  
Sherlin Rosita. A ◽  
...  
Keyword(s):  
Binding Energy ◽  
Rna Polymerase ◽  
In Silico ◽  
Biological Activities ◽  
The Novel ◽  
Rna Dependent Rna Polymerase ◽  
Ligand Interactions ◽  
Novel Coronavirus ◽  
Site Binding ◽  
The Ideal

Isatin (1H-indole-2,3-dione)-containing compounds have been shown to possess several remarkable biological activities. We had previously explored a few isatin-based imidazole derivatives for their predicted dual activity against both inflammation and cancer. We explored 47 different isatin-based derivatives (IBDs) for other potential biological activities using in silico tools and found them to possess anti-viral activity. Using AUTODOCK tools, the binding site, binding energy, inhibitory constant/Ki and receptor-ligand interactions for each of the compounds was analyzed against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The partition coefficient (logP) values were predicted using MedChem Designer tool. Based on the best Ki, binding energy and the ideal range of logP (between 1.0-3.0), 10 out of total 47 compounds were deemed to be prospective RdRp inhibitors. Some of these compounds gave better Ki, binding energy and logP values when compared to standard RdRp inhibitors such as remdesivir (Ki = 15.61 μM, logP = 2.2; binding energy = -6.95), a clinically approved RdRp inhibitor which is widely used for critical care of COVID-19 patients. The same in silico parameters were assessed for 9 other popular RdRp inhibitors (other than remdesivir), which were earlier used to target RdRp of other viruses, and are now repurposed to target SARS-CoV-2 RdRp. The results showed that the 10 selected isatin-based derivatives (IBDs) could be further explored for activity against SARS-Cov-2. In the present study we evaluated the efficacy of these compounds in silico.

Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

2020 ◽  
Author(s):  
Micael Davi Lima de Oliveira ◽  
Kelson Mota Teixeira de Oliveira
Keyword(s):  
World Health Organisation ◽  
World Health ◽  
Lung Cells ◽  
The Novel ◽  
High Modulation ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Viral Receptors ◽  
Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

Coronavirus: Towards controlling of the pandemic - Indian scenario

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 462-468
Author(s):  
Latika kothari ◽  
Sanskruti Wadatkar ◽  
Roshni Taori ◽  
Pavan Bajaj ◽  
Diksha Agrawal
Keyword(s):  
Control Measures ◽  
The Novel ◽  
Medical Treatments ◽  
Health Crisis ◽  
The Public ◽  
Infection Control Measures ◽  
The Social ◽  
Asking Questions ◽  
The Government ◽  
Novel Coronavirus

Coronavirus disease 2019 (COVID-19) is a communicable infection caused by the novel coronavirus resulting in severe acute respiratory syndrome coronavirus 2 (SARS-CoV). It was recognized to be a health crisis for the general population of international concern on 30th January 2020 and conceded as a pandemic on 11th March 2020. India is taking various measures to fight this invisible enemy by adopting different strategies and policies. To stop the COVID-19 from spreading, the Home Affairs Ministry and the health ministry, of India, has issued the nCoV 19 guidelines on travel. Screening for COVID-19 by asking questions about any symptoms, recent travel history, and exposure. India has been trying to get testing kits available. The government of India has enforced various laws like the social distancing, Janata curfew, strict lockdowns, screening door to door to control the spread of novel coronavirus. In this pandemic, innovative medical treatments are being explored, and a proper vaccine is being hunted to deal with the situation. Infection control measures are necessary to prevent the virus from further spreading and to help control the current situation. Thus, this review illustrates and explains the criteria provided by the government of India to the awareness of the public to prevent the spread of COVID-19.

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