scholarly journals Drug Repurposing Techniques in Viral Diseases

2021 ◽  
Author(s):  
Ran Zhang ◽  
Rick Oerlemans ◽  
Chao Wang ◽  
Lili Zhang ◽  
Matthew R. Groves
Keyword(s):  
Drug Development ◽  
Economic Activity ◽  
Molecular Mechanisms ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Drug Candidates ◽  
Short Period ◽  
Approved Drugs ◽  
Antiviral Medications ◽  
High Degree

Since the advent of the twentieth century, several severe virus outbreaks have occurred—H1N1 (1918), H2N2 (1957), H3N2 (1968), H1N1 (2009) and recently COVID-19 (2019)—all of which have posed serious challenges to public health. Therefore, rapid identification of efficacious antiviral medications is of ongoing paramount importance in combating such outbreaks. Due to the long cycle of drug development, not only in the development of a “safe” medication but also in mandated and extensive (pre)clinical trials before a drug can be safely licensed for use, it is difficult to access effective and safe novel antivirals. This is of particular importance in addressing infectious disease in appropriately short period of time to limit stress to ever more interlinked societal infrastructures; including interruptions to economic activity, supply routes as well as the immediate impact on health care. Screening approved drugs or drug candidates for antiviral activity to address emergent diseases (i.e. repurposing) provides an elegant and effective strategy to circumvent this problem. As such treatments (in the main) have already received approval for their use in humans, many of their limitations and contraindications are well known, although efficacy against new diseases must be shown in appropriate laboratory trials and clinical studies. A clear in this approach in the case of antivirals is the “relative” simplicity and a high degree of conservation of the molecular mechanisms that support viral replication—which improves the chances for a functional antiviral to inhibit replication in a related viral species. However, recent experiences have shown that while repurposing has the potential to identify such cases, great care must be taken to ensure a rigourous scientific underpinning for repurposing proposals. Here, we present a brief explanation of drug repurposing and its approaches, followed by an overview of recent viral outbreaks and associated drug development. We show how drug repurposing and combination approaches have been used in viral infectious diseases, highlighting successful cases. Special emphasis has been placed on the recent COVID-19 outbreak, and its molecular mechanisms and the role repurposing can/has play(ed) in the discovery of a treatment.

scholarly journals COVID-19 Knowledge Extractor (COKE): A Tool and a Web Portal to Extract Drug - Target Protein Associations from the CORD-19 Corpus of Scientific Publications on COVID-19

2020 ◽  
Author(s):  
Daniel Korn ◽  
Vera Pervitsky ◽  
Tesia Bobrowski ◽  
Vinicius Alves ◽  
Charles Schmitt ◽  
...  
Keyword(s):  
Web Application ◽  
Drug Target ◽  
Drug Repurposing ◽  
Research Literature ◽  
Target Protein ◽  
Scientific Publications ◽  
Biological Targets ◽  
Drug Candidates ◽  
Short Period ◽  
Approved Drugs

<p><b>Objective:</b> The COVID-19 pandemic has catalyzed a widespread effort to identify drug candidates and biological targets of relevance to SARS-COV-2 infection, which resulted in large numbers of publications on this subject. We have built the <b><u>CO</u></b>VID-19 <b><u>K</u></b>nowledge <b><u>E</u></b>xtractor (COKE), a web application to extract, curate, and annotate essential drug-target relationships from the research literature on COVID-19 to assist drug repurposing efforts.</p> <p><b>Materials and Methods:</b> SciBiteAI ontological tagging of the COVID Open Research Dataset (CORD-19), a repository of COVID-19 scientific publications, was employed to identify drug-target relationships. Entity identifiers were resolved through lookup routines using UniProt and DrugBank. A custom algorithm was used to identify co-occurrences of protein and drug terms, and confidence scores were calculated for each entity pair.</p> <p><b>Results:</b> COKE processing of the current CORD-19 database identified about 3,000 drug-protein pairs, including 29 unique proteins and 500 investigational, experimental, and approved drugs. Some of these drugs are presently undergoing clinical trials for COVID-19.</p> <p><b>Discussion:</b> The rapidly evolving situation concerning the COVID-19 pandemic has resulted in a dramatic growth of publications on this subject in a short period. These circumstances call for methods that can condense the literature into the key concepts and relationships necessary for insights into SARS-CoV-2 drug repurposing. </p> <p><b>Conclusion:</b> The COKE repository and web application deliver key drug - target protein relationships to researchers studying SARS-CoV-2. COKE portal may provide comprehensive and critical information on studies concerning drug repurposing against COVID-19. COKE is freely available at <a href="https://coke.mml.unc.edu/">https://coke.mml.unc.edu/</a> and the code is available at <a href="https://github.com/DnlRKorn/CoKE">https://github.com/DnlRKorn/CoKE</a>. </p>

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 COVID-19 Knowledge Extractor (COKE): A Tool and a Web Portal to Extract Drug - Target Protein Associations from the CORD-19 Corpus of Scientific Publications on COVID-19

2020 ◽  
Author(s):  
Daniel Korn ◽  
Vera Pervitsky ◽  
Tesia Bobrowski ◽  
Vinicius Alves ◽  
Charles Schmitt ◽  
...  
Keyword(s):  
Web Application ◽  
Drug Target ◽  
Drug Repurposing ◽  
Research Literature ◽  
Target Protein ◽  
Scientific Publications ◽  
Biological Targets ◽  
Drug Candidates ◽  
Short Period ◽  
Approved Drugs

<p><b>Objective:</b> The COVID-19 pandemic has catalyzed a widespread effort to identify drug candidates and biological targets of relevance to SARS-COV-2 infection, which resulted in large numbers of publications on this subject. We have built the <b><u>CO</u></b>VID-19 <b><u>K</u></b>nowledge <b><u>E</u></b>xtractor (COKE), a web application to extract, curate, and annotate essential drug-target relationships from the research literature on COVID-19 to assist drug repurposing efforts.</p> <p><b>Materials and Methods:</b> SciBiteAI ontological tagging of the COVID Open Research Dataset (CORD-19), a repository of COVID-19 scientific publications, was employed to identify drug-target relationships. Entity identifiers were resolved through lookup routines using UniProt and DrugBank. A custom algorithm was used to identify co-occurrences of protein and drug terms, and confidence scores were calculated for each entity pair.</p> <p><b>Results:</b> COKE processing of the current CORD-19 database identified about 3,000 drug-protein pairs, including 29 unique proteins and 500 investigational, experimental, and approved drugs. Some of these drugs are presently undergoing clinical trials for COVID-19.</p> <p><b>Discussion:</b> The rapidly evolving situation concerning the COVID-19 pandemic has resulted in a dramatic growth of publications on this subject in a short period. These circumstances call for methods that can condense the literature into the key concepts and relationships necessary for insights into SARS-CoV-2 drug repurposing. </p> <p><b>Conclusion:</b> The COKE repository and web application deliver key drug - target protein relationships to researchers studying SARS-CoV-2. COKE portal may provide comprehensive and critical information on studies concerning drug repurposing against COVID-19. COKE is freely available at <a href="https://coke.mml.unc.edu/">https://coke.mml.unc.edu/</a> and the code is available at <a href="https://github.com/DnlRKorn/CoKE">https://github.com/DnlRKorn/CoKE</a>. </p>

scholarly journals Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma

2020 ◽  
Author(s):  
Mohamed E. M. Saeed ◽  
Onat Kadioglu ◽  
Henry Johannes Greten ◽  
Adem Yildirim ◽  
Katharina Mayr ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Treatment Options ◽  
Drug Repurposing ◽  
Sequencing Data ◽  
Survival Times ◽  
Chemical Library ◽  
Ki 67 ◽  
Drug Candidates ◽  
Egfr Expression ◽  
Approved Drugs

SummaryBackground Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.

scholarly journals Computational guided approach for drug repurposing against SARS-CoV-2

2021 ◽  
Author(s):  
Jigisha Anand ◽  
Tanmay Ghildiyal ◽  
Aakanksha Madhwal ◽  
Rishabh Bhatt ◽  
Devvret Verma ◽  
...  
Keyword(s):  
Drug Targets ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Computational Docking ◽  
Drug Candidates ◽  
Docking Tool ◽  
Inhibitory Potential ◽  
Approved Drugs ◽  
Tract Infections

Background: In the current SARS-CoV-2 outbreak, drug repositioning emerges as a promising approach to develop efficient therapeutics in comparison to de novo drug development. The present investigation screened 130 US FDA-approved drugs including hypertension, cardiovascular diseases, respiratory tract infections (RTI), antibiotics and antiviral drugs for their inhibitory potential against SARS-CoV-2. Materials & methods: The molecular drug targets against SARS-CoV-2 proteins were determined by the iGEMDOCK computational docking tool. The protein homology models were generated through SWISS Model workspace. The pharmacokinetics of all the ligands was determined by ADMET analysis. Results: The study identified 15 potent drugs exhibiting significant inhibitory potential against SARS-CoV-2. Conclusion: Our investigation has identified possible repurposed drug candidates to improve the current modus operandi of the treatment given to COVID-19 patients.

scholarly journals Integrated Docking and Enhanced Sampling Based Selection of Repurposing Drugs for SARS-CoV-2 by Targeting Host Dependent Factors

2020 ◽  
Author(s):  
Amit Kumawat ◽  
Sadanandam Namsani ◽  
Debabrata Pramanik ◽  
Sudip Roy ◽  
Jayant K. Singh
Keyword(s):  
Regulatory Protein ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
High Throughput Analysis ◽  
Drug Candidates ◽  
Global Pandemic ◽  
Therapeutic Uses ◽  
Approved Drugs ◽  
Fda Approved Drugs

Since the onset of global pandemic, the most focused research currently in progress is the development of vaccine candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. Here, we investigate the drug repurposing strategies to counteract the coronavirus infection which involves several potential targetable host proteins involved in viral replication and disease progression. We report the high throughput analysis of literature-derived repurposing drug candidates that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies. In this work we have performed integrated molecular docking followed by molecular dynamics (MD) simulations and free energy calculations through an expedite insilico process where the number of screened candidates reduces sequentially at every step based on physicochemical information. We elucidate that in addition to the pre-clinical and FDA approved drugs that targets specific regulatory proteins, a range of chemical compounds (Nafamostat, Chloramphenicol, Ponatinib) binds to the other gene transcription and translation regulatory protein with higher affinity and may harbour potential for therapeutic uses.<br>

scholarly journals Multiple Drug-Induced Stress Responses Inhibit Formation of Escherichia coli Biofilms

2020 ◽  
Vol 86 (21) ◽  
Author(s):  
Nataliya A. Teteneva ◽  
Sergey V. Mart’yanov ◽  
María Esteban-López ◽  
Jörg Kahnt ◽  
Timo Glatter ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Stress Responses ◽  
Biofilm Formation ◽  
Molecular Mechanisms ◽  
Drug Repurposing ◽  
Bacterial Attachment ◽  
Bacterial Biofilm ◽  
Multiple Drug ◽  
Content Type ◽  
Approved Drugs

ABSTRACT In most ecosystems, bacteria exist primarily as structured surface-associated biofilms that can be highly tolerant to antibiotics and thus represent an important health issue. Here, we explored drug repurposing as a strategy to identify new antibiofilm compounds, screening over 1,000 compounds from the Prestwick Chemical Library of approved drugs for specific activities that prevent biofilm formation by Escherichia coli. Most growth-inhibiting compounds, which include known antibacterial but also antiviral and other drugs, also reduced biofilm formation. However, we also identified several drugs that were biofilm inhibitory at doses where only a weak effect or no effect on planktonic growth could be observed. The activities of the most specific antibiofilm compounds were further characterized using gene expression analysis, proteomics, and microscopy. We observed that most of these drugs acted by repressing genes responsible for the production of curli, a major component of the E. coli biofilm matrix. This repression apparently occurred through the induction of several different stress responses, including DNA and cell wall damage, and homeostasis of divalent cations, demonstrating that biofilm formation can be inhibited through a variety of molecular mechanisms. One tested drug, tyloxapol, did not affect curli expression or cell growth but instead inhibited biofilm formation by suppressing bacterial attachment to the surface. IMPORTANCE The prevention of bacterial biofilm formation is one of the major current challenges in microbiology. Here, by systematically screening a large number of approved drugs for their ability to suppress biofilm formation by Escherichia coli, we identified a number of prospective antibiofilm compounds. We further demonstrated different mechanisms of action for individual compounds, from induction of replicative stress to disbalance of cation homeostasis to inhibition of bacterial attachment to the surface. Our work demonstrates the potential of drug repurposing for the prevention of bacterial biofilm formation and suggests that also for other bacteria, the activity spectrum of antibiofilm compounds is likely to be broad.

Antidepressants and antipsychotic agents as repurposable oncological drug candidates

2020 ◽  
Vol 27 ◽  
Author(s):  
Michał Antoszczak ◽  
Anna Markowska ◽  
Janina Markowska ◽  
Adam Huczyński
Keyword(s):  
Drug Development ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Antipsychotic Agents ◽  
Therapeutic Action ◽  
Drug Candidates ◽  
New Strategy ◽  
The Central Nervous System ◽  
Medical Indications

: Drug repurposing, known also as drug repositioning/reprofiling, is a relatively new strategy for identification of alternative uses of well-known therapeutics that are outside the scope of their original medical indications. Such an approach might entail a number of advantages compared to standard de novo drug development, including less time needed to introduce the drug to the market, and lower costs. The group of compounds that could be considered as promising candidates for repurposing in oncology includes the central nervous system drugs, especially selected antidepressant and antipsychotic agents. In this article, we provide an overview of some antidepressants (citalopram, fluoxetine, paroxetine, sertraline) and antipsychotics (chlorpromazine, pimozide, thioridazine, trifluoperazine) that have the potential to be repurposed as novel chemotherapeutics in cancer treatment, as they have been found to exhibit preventive and/or therapeutic action in cancer patients. Nevertheless, although drug repurposing seems to be an attractive strategy to search for oncological drugs, we would like to clearly indicate that it should not replace the search for new lead structures, but only complement de novo drug development.

Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century

2020 ◽  
Vol 20 ◽  
Author(s):  
Nitesh Sanghai ◽  
Kashfia Shafiq ◽  
Geoffrey K. Tranmer
Keyword(s):  
Drug Discovery ◽  
Drug Repurposing ◽  
Compassionate Use ◽  
Drug Candidates ◽  
Working Day ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Day By Day ◽  
Potential Use

: Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).

scholarly journals Drug Repurposing of Approved Drugs Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine and Ergotamine for Combating COVID19

2020 ◽  
Author(s):  
Vishal Mevada ◽  
Pravin Dudhagara ◽  
Himani Gandhi ◽  
Nilam Vaghamshi ◽  
Urvisha Beladiya ◽  
...  
Keyword(s):  
Protein Structures ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Sequential Screening ◽  
Drug Molecules ◽  
Single Target ◽  
Approved Drugs ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Country Office

<p>Pneumonia of unknown cause detected in Wuhan, China was first reported to the WHO Country Office in China on 31 December 2019. The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. Currently, there is no Vaccine against COVID-19 pandemic and infection is spreading worldwide vary rapidly there is an exigent requirement of practicable drug treatment. Drug repurposing is one of the most promising approaches for that. Many reports are available with <i>in silico</i> drug repurposing but the majority of them engrossed on a single target. The present study aimed at screening the approved against Covid19 protein and extract the combination of operational comprehensively. A total of 1735 drug molecules against all COVID19 protein structures and sequential screening recognize the better potential of anti-HCV drugs over anti-HIV drugs. The study designated Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine Ergotamin as promising drug candidates for covid19 treatment. The computational analysis also reveled the better potential of proposed drugs over the currently used drug combination for COVID19 drugs. </p>

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