scholarly journals in silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

2020 ◽  
Author(s):  
Tianzi Wei ◽  
Hao Wang ◽  
Xueqing Wu ◽  
Yi Lu ◽  
Shenghui Guan ◽  
...  
Keyword(s):  
Drug Development ◽  
Binding Capacity ◽  
Drug Repurposing ◽  
Integrase Inhibitor ◽  
Spike Protein ◽  
Hiv Integrase ◽  
Spike Glycoprotein ◽  
High Binding ◽  
Potential Spike ◽  
Approved Drugs

Abstract COVID-19 has globally spread and has become a new pandemic, but there is still no effective drugs or vaccines to treat or prevent this disease. SARS-Cov-2 invades human cells through its spike proteins interacting with human ACE2 receptors. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with ACE2. In such an emergent situation, drug repurposing is a promising method for rapid drug development. Here, we selected around 15000 molecular candidates including FDA-approved drugs from DrugBank and natural compounds from TCMSP to perform virtual screening for potential molecules that can target viral spike protein based on its crystal structure. In this article, we present the top 20 molecules with high binding affinity with spike protein, of which, digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP, extracted from indigo naturalis and polygoni tinctorii foliu, have the highest docking scores. In addition, we also found that raltegravir, an HIV integrase inhibitor, has a relatively high binding score. Those molecules with high binding capacity to spike glycoprotein might be used by other researchers for further anti-COVID-19 drug development.

scholarly journals In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

2020 ◽  
Author(s):  
Tianzi Wei ◽  
Hao Wang ◽  
Xueqing Wu ◽  
Yi Lu ◽  
Shenghui Guan ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Integrase Inhibitor ◽  
Spike Protein ◽  
Hiv Integrase ◽  
Potential Spike ◽  
Indigo Naturalis ◽  
Approved Drugs ◽  
Effective Drugs ◽  
Glycoprotein Inhibitors ◽  
Spike Proteins

Abstract COVID-19 has globally spread and has become a new pandemic, but there are still no effective drugs or vaccines to treat or prevent this disease. SARS-CoV-2 invades human cells through its spike proteins interacting with human ACE2 receptors, which may cause severe respiratory syndrome. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with human ACE2. Facing such an urgent situation, drug repurposing is a promising strategy for rapid drug development. Here, we selected approximately 15000 molecular candidates, including FDA-approved drugs from DrugBank and natural compounds from TCMSP, to perform virtual screening for potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human ACE2 receptor and viral spike protein. We found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin, which is extracted from indigo naturalis and polygoni tinctorii foliu, in TCMSP had the highest docking scores. Note that indigo naturalis and the other herbs we found have been applied to prevent infectious diseases in traditional Chinese medicine. We also found that raltegravir, an HIV integrase inhibitor, has a relatively high binding affinity. All the docking results are presented in this article. Based on these docking results, further work will continue to identify potential molecules to prevent the spike protein from binding with the ACE2 receptor.Authors Tianzi Wei and Hao Wang contributed equally to this work.

scholarly journals COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Sepehr Ehsani
Keyword(s):  
Respiratory Infections ◽  
Binding Capacity ◽  
Sequence Similarity ◽  
Cytoplasmic Tail ◽  
Research Field ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Surface Receptors ◽  
Evolutionary Connection ◽  
Novel Coronavirus

Abstract The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans through its inhibition of the iron-exporting protein ferroportin. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.

scholarly journals Drug Repurposing: A Review

2021 ◽  
pp. 161-169
Author(s):  
Rani Teksinh Bhagat ◽  
Santosh Ramarao Butle
Keyword(s):  
Drug Development ◽  
Research And Development ◽  
Development Process ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
New Drugs ◽  
Preclinical Development ◽  
Therapeutic Uses ◽  
Original Application ◽  
Approved Drugs

The drug development is a very time consuming and complex process. Drug development Process is Expensive. Success rate for the new drug development is very small. In recent years, decreases the new drugs development. The powerful tools are developed to support the research and development (R&D) process is essential. The Drug repurposing are helpful for research and development process. The drug re-purposing as an approach finds new therapeutic uses for current candidates or existing candidates or approved drugs, different from its original application. The main aimed of Drug repurposing is to reduce costs and research time investments in Research & Development. It is used for the diagnosis and treatment of various diseases. Repositioning is important over traditional approaches and need for effective therapies. Drug re-purposing identifies new application for already banned or existing drugs from market. In drug design, drug repurposing plays important role, because it helps to preclinical development. It reducing time efforts, expenses and failures in drug discovery process. It is also called as drug repositioning, drug redirecting, drug reprofiling.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Nilotinib and Imatinib bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

scholarly journals Integrating gene expression and clinical data to identify drug repurposing candidates for hyperlipidemia and hypertension

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Patrick Wu ◽  
QiPing Feng ◽  
Vern Eric Kerchberger ◽  
Scott D. Nelson ◽  
Qingxia Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Development ◽  
Clinical Data ◽  
High Throughput ◽  
Research Program ◽  
Human Gene ◽  
Drug Repurposing ◽  
Therapeutic Effects ◽  
New Drug Development ◽  
Approved Drugs

AbstractDiscovering novel uses for existing drugs, through drug repurposing, can reduce the time, costs, and risk of failure associated with new drug development. However, prioritizing drug repurposing candidates for downstream studies remains challenging. Here, we present a high-throughput approach to identify and validate drug repurposing candidates. This approach integrates human gene expression, drug perturbation, and clinical data from publicly available resources. We apply this approach to find drug repurposing candidates for two diseases, hyperlipidemia and hypertension. We screen >21,000 compounds and replicate ten approved drugs. We also identify 25 (seven for hyperlipidemia, eighteen for hypertension) drugs approved for other indications with therapeutic effects on clinically relevant biomarkers. For five of these drugs, the therapeutic effects are replicated in the All of Us Research Program database. We anticipate our approach will enable researchers to integrate multiple publicly available datasets to identify high priority drug repurposing opportunities for human diseases.

scholarly journals In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

2020 ◽  
Vol 26 (9) ◽  
pp. 663-669 ◽  
Author(s):  
Tian-zi Wei ◽  
Hao Wang ◽  
Xue-qing Wu ◽  
Yi Lu ◽  
Sheng-hui Guan ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Spike Glycoprotein ◽  
In Silico Screening ◽  
Potential Spike ◽  
Glycoprotein Inhibitors

scholarly journals In silico synergistic drug repurposing for combating novel coronavirus (COVID-19) outbreaks

2020 ◽  
Author(s):  
Minjee Kim ◽  
Young Bong Kim
Keyword(s):  
Drug Development ◽  
Drug Combination ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Ppi Network ◽  
Target List ◽  
Drug Candidates ◽  
Novel Coronavirus ◽  
Approved Drugs

Abstract As the number of novel coronavirus (COVID-19) cases continues to rise, there is a global need for rapid drug development. In this study, we propose a systems pharmacology approach to reposition FDA-approved drug candidates for coronavirus, identify targets and suggest a synergistic drug combination using network pharmacology. We collected 67 genes associated with coronavirus, performed an enrichment analysis to obtain coronavirus-associated disease- pathway and constructed protein-protein interaction (PPI) network based on 67 genes. Total 37 significant disease-pathways were retrieved, and associated FDA-approved drugs were listed for drug repurposing candidates. Our PPI network showed 51 targets from 67 genes and identified IL6 and TNF as potential targets for coronavirus. From the FDA drug list, we selected four drugs that are experimentally used or studied for coronavirus to construct two- drug combinations. From six drug-drug networks, we identified hydroxychloroquine + ribavirin combination had the highest number of overlapping targets (IL6, IL2, IL10, CASP3, IFNA1) from PPI network target list, suggesting a potent synergistic drug combination for coronavirus. With the aim to support the rapid drug development, we suggest a new approach using systems-level drug repurposing for COVID-19 treatment.

scholarly journals Repurposing of Approved Drugs with Potential to Block SARS-CoV-2 Surface Glycoprotein Interaction with Host Receptor

2020 ◽  
Author(s):  
Abu Sajib
Keyword(s):  
In Silico ◽  
Potential Interaction ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Striking Similarity ◽  
Spike Glycoprotein ◽  
Human Lung Epithelial Cell ◽  
Angiotensin I Converting Enzyme ◽  
Human Lungs ◽  
Approved Drugs

Background: Respiratory transmission is the primary route of SARS-CoV-2 infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 spike glycoprotein for entry into human cells. A recent study reported absent to low ACE2 promoter activity in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE in human lungs compared to very low expression of ACE2. Methods: In silico tools were applied to assess potential interaction of SARS-CoV-2 surface spike protein with human ACE as well as predict the drugs that may block SARS-CoV-2 interaction with host receptor. Results: Although it is not obvious from the primary sequence alignment of ACE2 and its homolog ACE (also known as ACE1), comparison of X-ray crystallographic structures show striking similarity in the regions of these proteins which is known (for ACE2) to interact with the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Critical amino acids that mediate interaction with the viral spike protein in ACE2 are organized in the same order in ACE. In silico analyses predicts comparable interaction of SARS-CoV-2 spike protein with ACE2 and ACE. In addition, this study predicts and selects already approved drugs from a list of 1263, which may interfere with the binding of SARS-CoV-2 spike glycoprotein to ACE2 and/or ACE.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.Authors Alfonso Trezza and Daniele Iovinelli contributed equally to this work.

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