Repositioning of ligands that target spike glycoprotein as potential drugs against SARS-CoV-2

Abstract The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. It was identified drugs that binding to amino acids crucial for down to up conformational change, receptor recognition, and fusion of the viral membrane with the cell membrane. Results show some drugs that bind to hinge site amino acids (Varenicline, or even steroids as Betamethasone) while other drugs bind to crucial amino acids for RBM (Naldemedine, Atovaquone, Cefotetan) or FP (Edarbi, Maraviroc, Difluprednate); and highlights the Saquinavir that binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry (possible anti-COVID-19 drugs). Several drugs are in clinical studies; focused on another pharmacological target (candesartan, Atovaquone, Losartan, Maviroc and Ritonavir) in this work we propose an additional target, the spike glycoprotein. These results can impact in the proposal of treatments that can inhibit the first steps virus replication cycle.

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Repositioning of Ligands That Target the Spike Glycoprotein as Potential Drugs for SARS-CoV-2 in an In Silico Study

Molecules ◽

10.3390/molecules25235615 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5615

Author(s):

Gema Lizbeth Ramírez-Salinas ◽

Marlet Martínez-Archundia ◽

José Correa-Basurto ◽

Jazmín García-Machorro

Keyword(s):

Amino Acids ◽

Conformational Changes ◽

Viral Entry ◽

Drug Repositioning ◽

Specific Treatment ◽

Binding Motif ◽

Spike Glycoprotein ◽

Pharmacological Agents ◽

Docking Simulations ◽

Approved Drugs

The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA (Food and Drug Administration)-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. Drugs that bind to amino acids are crucial for conformational changes, receptor recognition, and fusion of the viral membrane with the cell membrane. The results revealed some drugs that bind to hinge site amino acids (varenicline, or steroids such as betamethasone while other drugs bind to crucial amino acids in the RBM (naldemedine, atovaquone, cefotetan) or FP (azilsartan, maraviroc, and difluprednate); saquinavir binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry as possible anti-COVID-19 drugs. Several drugs are in clinical studies; by focusing on other pharmacological agents (candesartan, atovaquone, losartan, maviroc and ritonavir) in this work we propose an additional target: the spike glycoprotein. These results can impact the proposed use of treatments that inhibit the first steps of the virus replication cycle.

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Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Molecules ◽

10.3390/molecules26113461 ◽

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.

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PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures

10.21203/rs.2.12791/v4 ◽

2020 ◽

Author(s):

Mhammad Asif Emon ◽

Daniel Domingo-Fernández ◽

Charles Tapley Hoyt ◽

Martin Hofmann-Apitius

Keyword(s):

Gene Expression ◽

Genome Wide Association Study ◽

Drug Repositioning ◽

Heterogeneous Data ◽

New Drugs ◽

Gwas Data ◽

Drug Candidates ◽

Gene Expression Signatures ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. Results: Here, we present a customizable workflow ( PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr .

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RepCOOL: computational drug repositioning via integrating heterogeneous biological networks

Journal of Translational Medicine ◽

10.1186/s12967-020-02541-3 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Ghazale Fahimian ◽

Javad Zahiri ◽

Seyed Shahriar Arab ◽

Reza H. Sajedi

Keyword(s):

Breast Cancer ◽

Biological Networks ◽

Drug Repositioning ◽

Machine Learning Algorithms ◽

New Drugs ◽

Stage Ii ◽

Cancer Stage ◽

New Drug ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Background It often takes more than 10 years and costs more than 1 billion dollars to develop a new drug for a particular disease and bring it to the market. Drug repositioning can significantly reduce costs and time in drug development. Recently, computational drug repositioning attracted a considerable amount of attention among researchers, and a plethora of computational drug repositioning methods have been proposed. This methodology has widely been used in order to address various medical challenges, including cancer treatment. The most common cancers are lung and breast cancers. Thus, suggesting FDA-approved drugs via drug repositioning for breast cancer would help us to circumvent the approval process and subsequently save money as well as time. Methods In this study, we propose a novel network-based method, named RepCOOL, for drug repositioning. RepCOOL integrates various heterogeneous biological networks to suggest new drug candidates for a given disease. Results The proposed method showed a promising performance on benchmark datasets via rigorous cross-validation. The final drug repositioning model has been built based on a random forest classifier after examining various machine learning algorithms. Finally, in a case study, four FDA approved drugs were suggested for breast cancer stage II. Conclusion Results show the potency of the proposed method in detecting true drug-disease relationships. RepCOOL suggested four new drugs for breast cancer stage II namely Doxorubicin, Paclitaxel, Trastuzumab, and Tamoxifen.

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A Drug Repositioning Approach Reveals that Streptococcus mutans Is Susceptible to a Diverse Range of Established Antimicrobials and Nonantibiotics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01674-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 5

Author(s):

S. Saputo ◽

R. C. Faustoferri ◽

R. G. Quivey

Keyword(s):

Streptococcus Mutans ◽

Biofilm Formation ◽

Drug Repositioning ◽

Drug Screen ◽

Biofilm Inhibition ◽

Diverse Range ◽

Content Type ◽

Multispecies Biofilm ◽

Approved Drugs ◽

Fda Approved Drugs

ABSTRACT Streptococcus mutans is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. An adenylate kinase-based assay was optimized for S. mutans to detect cell lysis when exposed to the Selleck library (Selleck Chemical, Houston, TX) of 853 FDA-approved drugs in, to our knowledge, the first high-throughput drug screen in S. mutans. We found 126 drugs with activity against S. mutans planktonic cultures, and they were classified into six categories: antibacterials (61), antineoplastics (23), ion channel effectors (9), other antimicrobials (7), antifungals (6), and other (20). These drugs were also tested for activity against S. mutans biofilm cultures, and 24 compounds were found to inhibit biofilm formation, 6 killed preexisting biofilms, 84 exhibited biofilm inhibition and killing activity, and 12 had no activity against biofilms. The activities of 9 selected compounds that exhibited antimicrobial activity were further characterized for their activity against S. mutans planktonic and biofilm cultures. Together, our results suggest that S. mutans exhibits a susceptibility profile to a diverse array of established and novel antibacterials.

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Evaluation of Yashtimadhu (Glycyrrhiza glabra) active Phytochemicals Against Novel Coronavirus (SARS-CoV-2)

10.21203/rs.3.rs-26480/v1 ◽

2020 ◽

Author(s):

Dharmendra Kumar Maurya

Keyword(s):

Viral Entry ◽

Virus Disease ◽

Scientific Basis ◽

Docking Studies ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus emerged from Wuhan, China in December 2019. It has spread to more than 205 countries and become pandemic now. Currently, there are no FDA approved drugs or vaccines available and hence several studies are going on in search of suitable drug that can target viral proteins or host receptor for the prevention and management of COVID-19. The search for plant-based anti-viral agents against the SARS-CoV-2 is promising because several of plants have been shown to possess anti-viral activities against different viruses. Here, we used molecular docking approach to explore the use of Indian Ayurvedic herbs, Yashtimadhu in prevention and management of COVID-19. In the present study we have evaluated the effectiveness of phytochemicals found in Yashtimadhu against Main Protease (Mpro), Spike (S) protein and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor and furin protease. Apart from this, we have also performed in-silico drug-likeness and predicted pharmacokinetics of the selected phytochemicals found in the Yashtimadhu. Our study shows that several phytochemicals found in this plant have potential to bind with important proteins of SARS-CoV-2 which are essential for viral infection and replication. Overall our study provides scientific basis in terms of binding of active ingredients present in Yashtimadhu with SARS-CoV-2 target proteins. Our docking studies reveal that Yashtimadhu may inhibit the viral severity by interfering with viral entry as well as its multiplication in the infected persons. Thus Yashtimadhu may be helpful in the prevention and management of the COVID-19.

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TMPRSS2 Transcriptional Inhibition as a Therapeutic Strategy for COVID-19

10.20944/preprints202003.0360.v2 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xinchen Wang ◽

Ryan Dhindsa ◽

Gundula Povysil ◽

Anthony Zoghbi ◽

Joshua Motelow ◽

...

Keyword(s):

Viral Entry ◽

Therapeutic Strategy ◽

Treatment Options ◽

Human Populations ◽

Expression Data ◽

Transcriptional Inhibition ◽

Transcriptional Modulators ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Therapeutic Avenue

There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. In mouse, knockout of tmprss2 led to protection against SARS-CoV-1 with no deleterious phenotypes, and in human populations genetic loss of TMPRSS2 does not appear to be selected against. Here, we mined publicly available gene expression data to identify several compounds that down-regulate TMPRSS2. Recognizing the need for immediately available treatment options, we focused on FDA-approved drugs. We found 20 independent studies that implicate estrogenic and androgenic compounds as transcriptional modulators of TMPRSS2, suggesting these classes of drugs may be promising therapeutic candidates for clinical testing and observational studies of COVID-19. We also note that expression of TMPRSS2 is highly variable and skewed in humans, with a minority of individuals having extremely high expression. Combined with literature showing that inhibition of TMPRSS2 protease activity reduces SARS-CoV-2 viral entry in human cells, our results raise the hypothesis that modulation of TMPRSS2 expression is a promising therapeutic avenue for COVID-19.

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Repurposing FDA-Approved Drugs for COVID-19 Using a Data-Driven Approach

10.26434/chemrxiv.12148764.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Rodrigo R. R. Duarte ◽

Dennis C. Copertino Jr. ◽

Luis P. Iñiguez ◽

Jez L. Marston ◽

Douglas F. Nixon ◽

...

Keyword(s):

Clinical Trials ◽

Drug Repositioning ◽

Data Driven ◽

Transcriptional Signature ◽

Lung Carcinoma Cells ◽

Main Protease ◽

Data Driven Approach ◽

Approved Drugs ◽

Fda Approved Drugs

<p>There have been more than 116,000 recorded deaths worldwide to-date caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19), and over 1.8 million individuals are currently infected. Although there are now hundreds of clinical trials for COVID-19, there are currently no effective licensed treatments, while the numbers of infected individuals continue to rise at an exponential rate in many parts of the world. Here, we used a data-driven approach utilizing connectivity mapping and the transcriptional signature of lung carcinoma cells infected with SARS-CoV-2, to search for drugs across the spectrum of medicine that have repurposing potential for treating COVID-19. We also performed chemoinformatic analyses to test whether the identified compounds were predicted to physically interact with the SARS-CoV-2 RNA-dependent RNA polymerase or main protease enzymes. Our study identified commonly prescribed FDA-approved molecules as important candidates for drug repositioning against COVID-19, including flupentixol, reserpine, fluoxetine, trifluoperazine, sunitinib, atorvastatin, raloxifene, butoconazole, and metformin. These drugs should not be taken for treating or preventing COVID-19 without a doctor’s advice, as further research and clinical trials are now needed to elucidate their efficacy for this purpose.</p>

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Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00819-20 ◽

2020 ◽

Vol 64 (7) ◽

Cited By ~ 101

Author(s):

Sangeun Jeon ◽

Meehyun Ko ◽

Jihye Lee ◽

Inhee Choi ◽

Soo Young Byun ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Drug Repositioning ◽

Antiviral Drug ◽

Drug Candidates ◽

Global Challenge ◽

Feasible Option ◽

Approved Drugs ◽

Fda Approved Drugs

ABSTRACT Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.

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Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning (Version 2)

10.26434/chemrxiv.12049647 ◽

2020 ◽

Author(s):

Ayman Farag ◽

Ping Wang ◽

Mahmoud Ahmed ◽

Hesham Sadek

Keyword(s):

Drug Repositioning ◽

Substrate Binding ◽

Binding Pocket ◽

Binding Energies ◽

Binding Modes ◽

Substrate Binding Pocket ◽

Protease Enzyme ◽

Starting Point ◽

Approved Drugs ◽

Fda Approved Drugs

The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugs against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket focusing on two potential sites (central and terminal sites) to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substrate-binding pocket. The top hits bound to the central site of Mpro substrate-binding pocket include antiviral drugs such as Darunavir, Nelfinavir and Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. In addition, the top hits bound to the terminal site of Mpro substrate-binding pocket include the anti-asthma drug Montelukast and the anti-histaminic Fexofenadine among others. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.<br>

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