scholarly journals Drug Repurposing in Neurological Diseases: Opportunities and Challenges

2020 ◽  
Author(s):  
Xiao-Yuan Mao
Keyword(s):  
Neurological Diseases ◽  
Drug Repurposing ◽  
New Drugs ◽  
Drug Candidates ◽  
Therapeutic Benefits ◽  
Therapeutic Value ◽  
Traditional Drug ◽  
Approved Drugs ◽  
Structure Complexity ◽  
Refractory Diseases

Drug repurposing or repositioning refers to “studying of clinically approved drugs in one disease to see if they have therapeutic value and do not trigger side effects in other diseases.” Nowadays, it is a vital drug discovery approach to explore new therapeutic benefits of existing drugs or drug candidates in various human diseases including neurological disorders. This approach overcomes the shortage faced during traditional drug development in grounds of financial support and timeline. It is especially hopeful in some refractory diseases including neurological diseases. The feature that structure complexity of the nervous system and influence of blood–brain barrier permeability often becomes more difficult to develop new drugs in neuropathological conditions than diseases in other organs; therefore, drug repurposing is particularly of utmost importance. In this chapter, we discuss the role of drug repurposing in neurological diseases and make a summarization of repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also outline drug repurposing approaches and limitations and challenges in the future investigations.

scholarly journals PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures

2020 ◽  
Author(s):  
Mhammad Asif Emon ◽  
Daniel Domingo-Fernández ◽  
Charles Tapley Hoyt ◽  
Martin Hofmann-Apitius
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Drug Repositioning ◽  
Heterogeneous Data ◽  
New Drugs ◽  
Gwas Data ◽  
Drug Candidates ◽  
Gene Expression Signatures ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. Results: Here, we present a customizable workflow ( PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr .

scholarly journals Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

2020 ◽  
Author(s):  
Vijayakumar Balakrishnan ◽  
Karthik Lakshminarayanan
Keyword(s):  
Vaccine Development ◽  
New Drugs ◽  
World Health ◽  
Wuhan City ◽  
Drug Candidates ◽  
Human Contact ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

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 Repurposing of Linagliptin Similar FDA Approved Drugs as Antidiabetic Agents

2021 ◽  
Vol 10 (4) ◽  
pp. 2766-2776
Keyword(s):  
Metabolic Diseases ◽  
Drug Repurposing ◽  
Binding Energies ◽  
New Drugs ◽  
Epidemic Disease ◽  
Global Epidemic ◽  
Dpp Iv ◽  
Epidemiology Data ◽  
Approved Drugs ◽  
Fda Approved Drugs

Diabetes mellitus is considered a global epidemic disease and is one of the metabolic diseases affecting individuals irrespective of age, sex, and race. According to WHO epidemiology data, the DM prevalence globally has risen from 4.7% to 8.5 % from 1980 to 2014. The discovery of new drugs has become more challenging for the pharmaceutical companies even though major investment has made in the conventional drug discovery approach. To overcome this obstacle, drug repurposing is an emerging field of development where an existing drug is tested for treatment. Successful repurposing of zidovudine, minoxidil, sildenafil, celecoxib, aspirin, and topiramate are reported for respective diseases. The present study focused on the computational approach to fetch the favorable drugs from the pool of FDA approved drugs against diabetes. Initially, structure similarity studies were carried out by using the template structure of standard DPP-IV inhibitor, Linagliptin. About 26 drugs have shown similarity, and the other 14 drugs filtered by Pass Online binding energies are determined by molecular docking at the binding site of DPP-IV (PDB ID 2i78). Among these, pranlukast and mirabegron have shown good binding interactions with dock scores of -13.81 and -13.06.

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>

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 Utilisation of the Prestwick Chemical Library®to identify drugs that inhibit the growth of Mycobacteria

2018 ◽  
Author(s):  
Panchali Kanvatirth ◽  
Rose E. Jeeves ◽  
Joanna Bacon ◽  
Gurdyal S. Besra ◽  
Luke J. Alderwick
Keyword(s):  
Drug Repurposing ◽  
Antimycobacterial Activity ◽  
Drug Regimen ◽  
New Drugs ◽  
Bacterial Disease ◽  
Drug Resistant ◽  
Chemical Library ◽  
Incidence And Mortality ◽  
Approved Drugs ◽  
New Treatments

AbstractTuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library®using a GFP microplate assay. Drugs were screened against GFP expressing strains ofMycobacterium smegmatisandMycobacterium bovisBCG as surrogates forMycobacterium tuberculosis,the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against bothM. smegmatisandM. bovisBCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes.

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>

scholarly journals Drug Repurposing: A Paradigm Shift in Drug Discovery

2020 ◽  
Vol 5 (04) ◽  
pp. 60-68
Author(s):  
Saravanan Jayaram ◽  
Emdormi Rymbai ◽  
Deepa Sugumar ◽  
Divakar Selvaraj
Keyword(s):  
Drug Discovery ◽  
Success Rate ◽  
Chemical Structure ◽  
Target Identification ◽  
Drug Repurposing ◽  
New Drugs ◽  
Attractive Option ◽  
Traditional Drug ◽  
Repurposed Drugs

The traditional methods of drug discovery and drug development are a tedious, complex, and costly process. Target identification, target validation; lead identification; and lead optimization are a lengthy and unreliable process that further complicates the discovery of new drugs. A study of more than 15 years reports that the success rate in the discovery of new drugs in the fields of ophthalmology, cardiovascular, infectious disease, and oncology to be 32.6%, 25.5%, 25.2% and 3.4%, respectively. A tedious and costly process coupled with a very low success rate makes the traditional drug discovery a less attractive option. Therefore, an alternative to traditional drug discovery is drug repurposing, a process in which already existing drugs are repurposed for conditions other than which were originally intended. Typical examples of repurposed drugs are thalidomide, sildenafil, memantine, mirtazapine, mifepristone, etc. In recent times, several databases have been developed to hasten drug repurposing based on the side effect profile, the similarity of chemical structure, and target site. This work reviews the pivotal role of drug repurposing in drug discovery and the databases currently available for drug repurposing.

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