scholarly journals In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Franck Touret ◽  
Magali Gilles ◽  
Karine Barral ◽  
Antoine Nougairède ◽  
Jacques van Helden ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Antiarrhythmic Agents ◽  
Chemical Library ◽  
New Information ◽  
Cns Drugs ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Abstract A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.

scholarly journals In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

2020 ◽  
Author(s):  
Franck Touret ◽  
Magali Gilles ◽  
Karine Barral ◽  
Antoine Nougairède ◽  
Etienne Decroly ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chemical Composition ◽  
In Vitro Screening ◽  
Short Term ◽  
Chemical Library ◽  
New Information ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

SummaryA novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development. In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay. 90 compounds were identified. The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials. The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds. Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2<EC50<20µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study could contribute to the short-term repurposing of drugs against 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 A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

2021 ◽  
Vol 22 (22) ◽  
pp. 12502
Author(s):  
Shoji Kokubo ◽  
Shinobu Ohnuma ◽  
Megumi Murakami ◽  
Haruhisa Kikuchi ◽  
Shota Funayama ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Atp Hydrolysis ◽  
Pheophorbide A ◽  
Chemical Library ◽  
Hct 116 ◽  
Potential Inhibitors

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

scholarly journals Repurposing drugs for treatment of SARS-CoV-2 infection: Computational design insights into mechanisms of action

2020 ◽  
Author(s):  
Shubhangi Kandwal ◽  
Darren Fayne
Keyword(s):  
Human Life ◽  
Drug Repurposing ◽  
Computational Design ◽  
Therapeutic Interventions ◽  
The Novel ◽  
Protein Targets ◽  
Novel Coronavirus ◽  
Approved Drugs

Abstract The COVID-19 pandemic has negatively affected human life globally. It has led to economic crises and health emergencies across the world, spreading rapidly among the human population and has caused many deaths. Currently, there are no treatments available for COVID-19 so there is an urgent need to develop therapeutic interventions that could be used against the novel coronavirus infection. In this research, we used computational drug design technologies to repurpose existing drugs as inhibitors of SARS-CoV-2 viral proteins. The Broad Institute’s Drug Repurposing Hub consists of in-development/approved drugs and was computationally screened to identify potential hits which could inhibit protein targets encoded by the SARS-CoV-2 genome. By virtually screening the Broad collection, using rationally designed pharmacophore features, we identified molecules which may be repurposed against viral nucleocapsid and non-structural proteins. The pharmacophore features were generated after careful visualisation of the interactions between co-crystalised ligands and the protein binding site. The ChEMBL database was used to determine the compound’s level of inhibition of SARS-CoV-2 and correlate the predicted viral protein target with whole virus in vitro data. The results from this study may help to accelerate drug development against COVID-19 and the hit compounds should be progressed through further in vitro and in vivo studies on SARS-CoV-2.

scholarly journals Molecular Docking Study of COVID-19 Main Protease with Clinically Approved Drugs

2020 ◽  
Author(s):  
TACHOUA Wafa ◽  
KABRINE Mohamed
Keyword(s):  
Docking Study ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Study ◽  
In Vivo Evaluation ◽  
Binding Cavity ◽  
Approved Drugs ◽  
Potential Inhibitors

<p>A novel strain of coronavirus, namely, Corona Virus Infection Disease 19 has been identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor we performed docking studies on the main virus protease with eight drugs belonging to four pharmacological classes: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. These two compounds revealed a minimum binding energy of -8.87 and -8.71 Kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Lymecycline and Mizolastine interact with specific residues in substrate binding cavity. Thus, Lymecycline and Mizolastione may serve as a tool to fight COVID-19 disease. However, this data need further in vitro and in vivo evaluation to repurpose these two drugs against COVID-19 disease.</p>

scholarly journals Phytochemicals of Rhus spp. as Potential Inhibitors of the SARS-CoV-2 Main Protease: Molecular Docking and Drug-Likeness Study

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Yousery E. Sherif ◽  
Sami A. Gabr ◽  
Nasser M. Hosny ◽  
Ahmad H. Alghadir ◽  
Rayan Alansari
Keyword(s):  
Molecular Docking ◽  
Specific Treatment ◽  
Polyphenolic Compounds ◽  
Protease Enzyme ◽  
Main Protease ◽  
Synthetic Accessibility ◽  
Novel Coronavirus ◽  
Potential Inhibitors

Background. The outbreak of coronavirus disease 2019 (COVID-19) induced by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in China and spread to cover the entire world with an ongoing pandemic. The magnitude of the situation and the fast spread of the new and deadly virus, as well as the lack of specific treatment, led to a focus on research to discover new therapeutic agents. Aim. In this study, we explore the potential inhibitory effects of some active polyphenolic constituents of Rhus spp. (sumac) against the SARS-CoV-2 main protease enzyme (Mpro; 6LU7). Methods. 26 active polyphenolic compounds of Rhus spp. were studied for their antiviral activity by molecular docking, drug likeness, and synthetic accessibility score (SAS) as inhibitors against the SARS-CoV-2 Mpro. Results. The results show that all tested compounds of sumac provided good interaction with the main active site of SARS-CoV-2 Mpro, with better, lower molecular docking energy (kcal/mol) compared to the well-known drugs chloroquine and favipiravir (Avigan). Only six active polyphenolic compounds of Rhus spp. (sumac), methyl 3,4,5-trihydroxybenzoate, (Z)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-2-hydroxyprop-2-en-1-one, (Z)-2-(3,4-dihydroxybenzylidene)-6-hydroxybenzofuran-3(2H)-one, 3,5,7-trihydroxy-2-(4-hydroxyphenyl)chroman-4-one, 2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chroman-4-one, and 3,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, were proposed by drug likeness, solubility in water, and SAS analysis as potential inhibitors of Mpro that may be used for the treatment of COVID-19. Conclusion. Six phenolic compounds of Rhus spp. are proposed for synthesis as potential inhibitors against Mpro and have potential for the treatment of COVID-19. These results encourage further in vitro and in vivo investigations of the proposed ligands and research on the preventive use of Rhus spp. against SARS-CoV-2.

scholarly journals In Silico Prediction and Structure Based Multitargeted Molecular Docking Analysis of Selected Bioactive Compounds Against Mucormycosis

2021 ◽  
Author(s):  
Premnath Madanagopal ◽  
Nagarjun Ramprabhu ◽  
Rahul Jagadeesan
Keyword(s):  
Bioactive Compounds ◽  
In Silico ◽  
Optimization Techniques ◽  
Rhizopus Delemar ◽  
Toxicity Risk ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Second Wave

Abstract Background: During the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosisto have contributed to the rise and it has been declared an epidemic in several states of India.Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases.Results: We chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein-ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs, and natural bioactive compounds. ADME parameters, Toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins(CotH3: -10.2 kcal/mol Lanosterol 14 alpha-demethylase: -10.9 kcal/mol Mucoricin:-8.6 kcal/mol).Conclusions: In summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimization techniques and in-vitro and in-vivo studies.

scholarly journals MOLECULAR DOCKING AND SCREENING OF DRUGS FOR 6LU7 PROTEASE INHIBITOR AS A POTENTIAL TARGET FOR COVID-19

2022 ◽  
pp. 100-105
Author(s):  
MANOJ GADEWAR ◽  
BHARAT LAL
Keyword(s):  
Molecular Docking ◽  
Data Bank ◽  
Docking Study ◽  
In Vivo Studies ◽  
Molecular Docking Study ◽  
Potential Target ◽  
Novel Coronavirus ◽  
Potential Inhibitors

Objective: The aim of present investigation is docking of various existing antiviral, anti-tubercular and anti-malarial drugs on 6LU7 receptor of SARS-CoV-2 in the treatment of COVID-19. Methods: In this study, the structure of coronavirus binding protein and ligands for various drugs were collected from the protein data bank and pub chem. Molecular docking was carried out using Schrodinger 9.0 software. In molecular docking study, 19 different drugs of various categories like antiviral, anti-malarial and anti-tubercular were investigated for analyzing binding to 6LU7 receptors of COVID-19. Results: The docking result showed a high affinity of zanamivir, montelukast, ramdesvir, ritonavir, cobicistat and favipravir to the 6LU7 receptor of novel coronavirus. Thus the combination of these drugs may be useful in preventing further infection and can be used as a potential target for further in vitro and in vivo studies of SARS-CoV-2. Conclusion: Treatment of COVID-19 has been challenge due to the non-availability of effective drug therapy. In this study, we reported drugs for targeting 6LU7 Mpro/3Clpro protein, which showed prominent effects as potential inhibitors of COVID-19 Mpro.

scholarly journals Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

2019 ◽  
Author(s):  
Andrea Cerquone Perpetuini ◽  
Alessio Reggio ◽  
Mauro Cerretani ◽  
Giulio Giuliani ◽  
Marisabella Santoriello ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipogenic Differentiation ◽  
Multipotent Stem Cells ◽  
Muscle Stem Cells ◽  
Myogenic Stem Cells ◽  
Approved Drugs ◽  
Muscle Homeostasis ◽  
Potential Inhibitors

AbstractMuscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in subconfluent FAPs. However, both drugs have a proadipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.

scholarly journals FDA Approved Drugs and Herbal Based Inhibitors Target SARS CoV-2 RNA Dependent RNA Polymerase

2021 ◽  
Vol 11 (3) ◽  
pp. 3811-3821
Keyword(s):  
Rna Polymerase ◽  
Drug Repurposing ◽  
World Health ◽  
In Vivo Studies ◽  
Rna Dependent Rna Polymerase ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Approved Drugs

The recent outburst of COVID-19 started as an epidemic in Wuhan city, China, in December 2019. It was declared a pandemic by World Health Organization on 30 January 2020. The rapid spread of the novel coronavirus leads to more deaths worldwide. Also, it has spared many lives in its second wave of disease in many countries. Although scientists had produced vaccines, it does not suit every human being, and they are getting infected again, which is due to a lack of extensive clinical trials. Also, drug repurposing is ineffective. There is a need for more research; using in silico methods may be the better option in the current situation to save the lives of virus-affected individuals. The drugs used for other diseases and herbal compounds might help target the coronavirus. In this study, a protein, RNA-dependent RNA polymerase (RdRp), was chosen as a target from the virus for molecular docking. It was docked against several drugs on the market and also several herbal compounds. This study will help further in vitro and in vivo studies with new lead compounds, new horizons for drugs in trials, and a new approach for Insilco analysis to treat COVID-19.

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