scholarly journals A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 277 ◽  
Author(s):  
Sean Ekins ◽  
Joel S. Freundlich ◽  
Megan Coffee
Keyword(s):  
Animal Studies ◽  
Computational Models ◽  
Ebola Virus ◽  
Protein Structures ◽  
Common Features ◽  
Molecular Features ◽  
Approved Drugs ◽  
Fda Approved Drugs

We are currently faced with a global infectious disease crisis which has been anticipated for decades. While many promising biotherapeutics are being tested, the search for a small molecule has yet to deliver an approved drug or therapeutic for the Ebola or similar filoviruses that cause haemorrhagic fever. Two recent high throughput screens published in 2013 did however identify several hits that progressed to animal studies that are FDA approved drugs used for other indications. The current computational analysis uses these molecules from two different structural classes to construct a common features pharmacophore. This ligand-based pharmacophore implicates a possible common target or mechanism that could be further explored. A recent structure based design project yielded nine co-crystal structures of pyrrolidinone inhibitors bound to the viral protein 35 (VP35). When receptor-ligand pharmacophores based on the analogs of these molecules and the protein structures were constructed, the molecular features partially overlapped with the common features of solely ligand-based pharmacophore models based on FDA approved drugs. These previously identified FDA approved drugs with activity against Ebola were therefore docked into this protein. The antimalarials chloroquine and amodiaquine docked favorably in VP35. We propose that these drugs identified to date as inhibitors of the Ebola virus may be targeting VP35. These computational models may provide preliminary insights into the molecular features that are responsible for their activity against Ebola virus in vitro and in vivo and we propose that this hypothesis could be readily tested.

scholarly journals FDA approved drugs as potential Ebola treatments

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 48 ◽  
Author(s):  
Sean Ekins ◽  
Megan Coffee
Keyword(s):  
Ebola Virus ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the search for treatments for the Ebola Virus, multiple screens of FDA drugs have led to the identification of several with promising in vitro activity. These compounds were not originally developed as antivirals and some have been further tested in mouse in vivo models. We put forward the opinion that some of these drugs could be evaluated further and move into the clinic as they are already FDA approved and in many cases readily available. This may be important if there is a further outbreak in future and no other therapeutic is available.

A screen of approved drugs and molecular probes identifies therapeutics with anti–Ebola virus activity

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra89-290ra89 ◽  
Author(s):  
Lisa M. Johansen ◽  
Lisa Evans DeWald ◽  
Charles J. Shoemaker ◽  
Benjamin G. Hoffstrom ◽  
Calli M. Lear-Rooney ◽  
...  
Keyword(s):  
Viral Entry ◽  
Ebola Virus ◽  
Molecular Probes ◽  
Infection Model ◽  
Channel Blockers ◽  
Emerging Infections ◽  
Virus Infections ◽  
Approved Drugs

Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration–approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

scholarly journals A platform utilizing Drosophila ovulation for nonhormonal contraceptive screening

2021 ◽  
Vol 118 (28) ◽  
pp. e2026403118
Author(s):  
Kewa Jiang ◽  
Jiyang Zhang ◽  
Yuping Huang ◽  
Yingzheng Wang ◽  
Shuo Xiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Unmet Need ◽  
Dependent Manner ◽  
Female Reproduction ◽  
Contraceptive Agents ◽  
Follicle Rupture ◽  
Approved Drugs ◽  
Fda Approved Drugs

A significant unmet need for new contraceptive options for both women and men remains due to side-effect profiles, medical concerns, and the inconvenience of many currently available contraceptive products. Unfortunately, the development of novel nonsteroidal female contraceptive medicine has been stalled in the last couple of decades due to the lack of effective screening platforms. Drosophila utilizes conserved signaling pathways for follicle rupture, a final step in ovulation that is essential for female reproduction. Therefore, we explored the potential to use Drosophila as a model to screen compounds that could inhibit follicle rupture and be nonsteroidal contraceptive candidates. Using our ex vivo follicle rupture assay, we screened 1,172 Food and Drug Administration (FDA)–approved drugs and identified six drugs that could inhibit Drosophila follicle rupture in a dose-dependent manner. In addition, we characterized the molecular actions of these drugs in the inhibition of adrenergic signaling and follicle rupture. Furthermore, we validated that three of the four drugs consistently inhibited mouse follicle rupture in vitro and that two of them did not affect progesterone production. Finally, we showed that chlorpromazine, one of the candidate drugs, can significantly inhibit mouse follicle rupture in vivo. Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these FDA-approved drugs as novel nonsteroidal contraceptive agents.

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 Déjà vu: Stimulating Open Drug Discovery for SARS-CoV-2

2020 ◽  
Author(s):  
Sean Ekins ◽  
Melina Mottin ◽  
Paulo R. P. S. Ramos ◽  
Bruna K. P. Sousa ◽  
Bruno Junior Neves ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Ebola Virus ◽  
Antiviral Drug ◽  
Open Science ◽  
Virus Rna ◽  
Deja Vu ◽  
Déjà Vu ◽  
Approved Drugs

In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the current outbreak of coronavirus disease which has been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). There is a strong sense of Déjà vu as the world is caught flat footed without effective treatments to administer to patients. Our team has been actively involved in several small molecule drug discovery efforts for the preceding virus outbreaks. In 2014 we used machine learning to identify 3 new molecules to test for the Ebola virus and these were subsequently shown to be active in vitro and in vivo. We have also been involved in open science approaches that leverage the community to help. In 2016 we launched the OpenZika project as an IBM World Community Grid Project that used distributed computing power of volunteers to dock large numbers of compounds into Zika and related flavivirus targets. This led us into several collaborations in which we validated computational predictions in vitro. With both of these initiatives there was some knowledge of the virus, many compounds had already been tested in the case of Ebola, whereas for Zika initially all we had was the virus RNA sequence. In the current SARS-CoV-2 outbreak, this was a completely new virus and the scientists in China and elsewhere have started from scratch. In the space of a few weeks since the outbreak is acknowledged to have started, there are now compounds suggested as active in vitro and molecules repurposed in clinical trials. While this has been impressive, we propose there may still be gaps in our approach to drug discovery for such outbreaks. There is an opportunity to repurpose additional approved drugs for this virus and we now suggest how these might be identified leveraging prior work on MERS-CoV, SARS-CoV and other viruses. We also describe some of the immense challenges and limitations of the open antiviral drug discovery approaches we have been involved in.

Potential Papain-like Protease Inhibitors against COVID-19: A Comprehensive In Silico Based Review

2021 ◽  
Vol 25 ◽  
Author(s):  
Neetu Agrawal ◽  
Shilpi Pathak ◽  
Ahsas Goyal
Keyword(s):  
In Silico ◽  
Chemical Compounds ◽  
Potential Candidate ◽  
In Vivo Experiments ◽  
Drug Databases ◽  
In Silico Studies ◽  
Approved Drugs ◽  
Fda Approved Drugs

: The entire world has been in a battle against the COVID-19 pandemic since its first appearance in December 2019. Thus researchers are desperately working to find an effective and safe therapeutic agent for its treatment. The multifunctional coronavirus enzyme papain-like protease (PLpro) is a potential target for drug discovery to combat the ongoing pandemic responsible for cleavage of the polypeptide, deISGylation, and suppression of host immune response. The present review collates the in silico studies performed on various FDA-approved drugs, chemical compounds, and phytochemicals from various drug databases and represents the compounds possessing the potential to inhibit PLpro. Thus this review can provide quick access to a potential candidate to medicinal chemists to perform in vitro and in vivo experiments who are thriving to find the effective agents for the treatment of COVID-19.

scholarly journals New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

2016 ◽  
Vol 60 (6) ◽  
pp. 3717-3729 ◽  
Author(s):  
Jourdan A. Andersson ◽  
Eric C. Fitts ◽  
Michelle L. Kirtley ◽  
Duraisamy Ponnusamy ◽  
Alex G. Peniche ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Bacterial Pathogens ◽  
Bactericidal Effect ◽  
Resistant Bacteria ◽  
Content Type ◽  
Broad Applicability ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulentYersinia pestisCO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventingY. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy inin vitroscreens, were chosen for further evaluation in a murine model of pneumonic plague to delineate ifin vitroefficacy could be translatedin vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect onY. pestisand having no modulating effect on crucialY. pestisvirulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified fromin vitroscreens, the therapeutic potential of TFP, the most efficacious drugin vivo, was evaluated in murine models ofSalmonella entericaserovar Typhimurium andClostridium difficileinfections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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 FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning

2020 ◽  
Author(s):  
Ayman Farag ◽  
Ping Wang ◽  
Mahmoud Ahmed ◽  
Hesham Sadek
Keyword(s):  
Drug Repositioning ◽  
Binding Energies ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Protease Enzyme ◽  
Starting Point ◽  
Approved Drugs ◽  
Fda Approved Drugs

<div>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</div><div>against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket 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 substratebinding pocket. The top hits include anti-viral drugs such as Darunavir, Nelfinavirand 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. 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.</div>

Selection of Active Antiviral Compounds Against Covid-19 Disease Targeting Coronavirus Endoribonuclease Nendou/NSP15 Via Ligand- Based Virtual Screening and Molecular Docking

2020 ◽  
Vol 17 ◽  
Author(s):  
Gaurav Joshi ◽  
Ramarao Poduri
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Antiviral Compounds ◽  
Clinical Level ◽  
Rapid Spread ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Selection Of

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against Covid-19. Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Results: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against Covid-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against Covid-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

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