scholarly journals High-throughput screening and evaluation of repurposed drugs targeting the SARS-CoV-2 main protease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yan Li ◽  
Jinyong Zhang ◽  
Zilei Duan ◽  
Ning Wang ◽  
Xiangcheng Sun ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Main Protease ◽  
Repurposed Drugs

scholarly journals Targeting the Main Protease of SARS‐CoV‐2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors

2021 ◽  
Author(s):  
Julian Breidenbach ◽  
Carina Lemke ◽  
Thanigaimalai Pillaiyar ◽  
Laura Schäkel ◽  
Ghazl Al Hamwi ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Main Protease

scholarly journals Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening

2020 ◽  
Author(s):  
Yan Li ◽  
Jinyong Zhang ◽  
Ning Wang ◽  
Haibo Li ◽  
Yun Shi ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Binding Capacity ◽  
Effective Means ◽  
Clinical Applications ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Clinical Drug ◽  
Specific Inhibitors

Abstract2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.

scholarly journals Current Trends in SPR Biosensing of SARS-CoV-2 Entry Inhibitors

Chemosensors ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 330
Author(s):  
Elba Mauriz ◽  
Laura M. Lechuga
Keyword(s):  
High Throughput Screening ◽  
Antiviral Agents ◽  
Host Cells ◽  
Binding Affinities ◽  
Entry Inhibitors ◽  
Antiviral Compounds ◽  
Current Trends ◽  
Main Protease ◽  
Emerging Risk ◽  
Repurposed Drugs

The emerging risk of viral diseases has triggered the search for preventive and therapeutic agents. Since the beginning of the COVID-19 pandemic, greater efforts have been devoted to investigating virus entry mechanisms into host cells. The feasibility of plasmonic sensing technologies for screening interactions of small molecules in real time, while providing the pharmacokinetic drug profiling of potential antiviral compounds, offers an advantageous approach over other biophysical methods. This review summarizes recent advancements in the drug discovery process of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) inhibitors using Surface Plasmon Resonance (SPR) biosensors. A variety of SPR assay formats are discussed according to the binding kinetics and drug efficacies of both natural products and repurposed drugs. Special attention has been given to the targeting of antiviral agents that block the receptor binding domain of the spike protein (RBD-S) and the main protease (3CLpro) of SARS-CoV-2. The functionality of plasmonic biosensors for high-throughput screening of entry virus inhibitors was also reviewed taking into account experimental parameters (binding affinities, selectivity, stability), potential limitations and future applications.

scholarly journals Virtual High Throughput Screening Based Prediction of Potential Drugs for COVID-19

2020 ◽  
Author(s):  
Sekhar Talluri
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Viral Infections ◽  
Genomic Sequence ◽  
Reproduction Number ◽  
Three Dimensional ◽  
Drug Repurposing ◽  
Dimensional Structure ◽  
Main Protease ◽  
Approved Drugs

SARS-CoV-2 is a betacoronavirus that was first identified during the Wuhan COVID-19 epidemic in 2019. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using virtual high throughput screening. The results of this study confirm earlier preliminary reports based on studies of homologs that some of the drugs approved for treatment of other viral infections also have the potential for treatment of COVID-19. Approved anti-viral drugs that target proteases were ranked for potential effectiveness against COVID-19 and novel candidates for drug repurposing were identified.

scholarly journals High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yan Li ◽  
Jinyong Zhang ◽  
Ning Wang ◽  
Yanjing Zhang ◽  
Yongjun Yang ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Binding Pocket ◽  
Substrate Binding Pocket ◽  
Stable Conformation ◽  
Cross Docking ◽  
Main Protease ◽  
Computer Based ◽  
Old Drugs

Abstract The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses. In the current study, we adopted a multiple cross-docking strategy against different crystal structures of SARS-CoV-2 Mpro to perform computer-based high-throughput virtual screening of possible inhibitors from a drug database using Autodock Vina and SeeSAR software, combined with our in-house automatic processing scripts. The KDs between screened candidates and Mpro were determined using Biacore. Seven drugs were found to fit the substrate-binding pocket of Mpro with a stable conformation, showing high KDs that ranged from 6.79E-7 M to 5.20E-5 M. Finally, mutagenesis studies confirmed that these drugs interact with Mpro specifically, suggesting that our method was reliable and convincing. Given the safety of these old drugs, they may serve as promising candidates to treat the infection of SARS-CoV-2. Our results also provide rational explanations for the behaviour of five drugs evaluated in clinical trials.

scholarly journals OR28-03 Drug Repurposing Identifies Inhibitors of the Proteostasis Network to Augment Radioiodine Uptake in Combinatorial Approaches Targeting Thyroid Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Martin L Read ◽  
Katie Brookes ◽  
Alice Fletcher ◽  
Caitlin E M Thornton ◽  
Mohammed Alshahrani ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
High Throughput ◽  
High Throughput Screening ◽  
Drug Repurposing ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Radioiodine Uptake ◽  
Repurposed Drugs ◽  
Thyroid Cancer Cells

Abstract New combinatorial drug strategies are urgently needed to improve radioiodine (RAI) uptake and efficiently ablate thyroid cancer cells, thereby reducing the risk of recurrent disease. Drug repurposing offers the promise of identifying already approved compounds capable of inducing sodium iodide symporter (NIS) function to enhance iodide uptake. However, a lack of thyroid cell-based assays amenable to high-throughput screening has limited progress. We utilised the mutated yellow fluorescent protein (YFP) as a surrogate biosensor of intracellular iodide and screened the Prestwick Chemical Library (1200 drugs; 95% approved) for quenching of YFP fluorescence. This allowed us to identify putative candidate drugs which increased iodide uptake >2 SD above mean. Categorisation of these revealed a high proportion of drugs that modulate the proteostasis network (19/48; ~40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 leading compounds based on their pharmacologic (AUC, EMAX and EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1 to 50 μM). Of importance, several repurposed drugs (e.g. ebastine, Prestwick N, Prestwick C and clotrimazole) in combination with the HDAC inhibitor vorinostat induced a robust enhancement in RAI uptake in thyroid cancer cells (TPC-1 and 8505C NIS+ve cells, up to 11-fold vs DMSO, P<0.001), which was significantly greater than using vorinostat alone (up to 3-fold, P<0.01). For clotrimazole, we designed 7 new chemical derivatives, 3 of which showed enhanced aqueous solubility and retained the ability to significantly enhance RAI uptake. TaqMan RT-PCR revealed that, in contrast to vorinostat, our repurposed drugs failed to alter NIS mRNA expression, highlighting post-transcriptional mechanisms. Critically, 11 repurposed drugs induced significant gains in RAI uptake in human primary thyroid cells (up to 4.1-fold; P<0.05), the most physiological setting for NIS function. In conclusion, we performed high-throughput screening and identified proteostasis modulators, as well as other repurposed drugs, that markedly enhance radioiodine uptake. Further clinical investigation of these drugs might offer new combinatorial approaches, especially with existing therapies, to improve the treatment of thyroid cancer.

Virtual High Throughput Screening to find suitable inhibitors for SARSCoV-2 Main Protease

2020 ◽  
Vol 18 ◽  
Author(s):  
Upasana Phukan ◽  
Nakul Neog ◽  
Minakshi Puzari ◽  
Mohan Sharma ◽  
Saurov Mahanta ◽  
...  
Keyword(s):  
High Throughput ◽  
Inhibitory Activity ◽  
High Throughput Screening ◽  
Binding Energies ◽  
Health Concern ◽  
Potential Candidate ◽  
Major Health ◽  
Discovery Studio ◽  
Main Protease ◽  
Potential Inhibitors

Background: SARS-CoV-2 virus which originated in Wuhan and quickly spread across various countries has taken the form of a pandemic. It is now a major health concern among everyone and finding a solution to this problem is of utmost importance. Understanding its origin, transmission, and interaction with different compounds is essential to find probable inhibitors. Objective: The objective of our study was to search for potential inhibitors of the main protease of SARS-CoV-2 and to access their drug-like properties. Methodology: In our study, 1909 ligands were filtered through Lipinski filter and ADMET properties along with mutagenic nature were analysed. They were screened for inhibitory activity against the Main Protease of SARS-CoV-2 using BIOVIA Discovery studio. Results: After virtual high throughput screening, two compounds- apigenin and N-(4-bromophenyl)-7-hydroxy-2- iminochromene-3-carboxamide were found to have promising binding energies as well as –CDOCKER energy scores compared to the reported inhibitor. Conclusion: Apigenin seems to be a potential candidate against the main protease of SARS-CoV-2 and must be considered for further experiments.

scholarly journals Targeting the Main Protease of SARS‐CoV‐2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors

2021 ◽  
Author(s):  
Julian Breidenbach ◽  
Carina Lemke ◽  
Thanigaimalai Pillaiyar ◽  
Laura Schäkel ◽  
Ghazl Al Hamwi ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Main Protease

scholarly journals Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening

2020 ◽  
Author(s):  
Wei Zhu ◽  
Miao Xu ◽  
Catherine Z. Chen ◽  
Hui Guo ◽  
Min Shen ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Drug Target ◽  
Cytopathic Effect ◽  
Drug Repurposing ◽  
Combination Therapies ◽  
Main Protease ◽  
Investigational Drugs ◽  
3Cl Protease ◽  
Viral Enzyme

AbstractThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C like protease (3CLpro), or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high throughput screening (qHTS) of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CLpro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC50 = 0.26 µM), Hydroxocobalamin (IC50 = 3.29 µM), Suramin sodium (IC50 = 6.5 µM), Z-DEVD-FMK (IC50 = 6.81 µM), LLL-12 (IC50 = 9.84 µM), and Z-FA-FMK (IC50 = 11.39 µM) are the most potent 3CLpro inhibitors. The activities of anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CLpro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients, and as starting points for chemistry optimization for new drug development.

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