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 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 CTKG: A Knowledge Graph for Clinical Trials

2021 ◽  
Author(s):  
Ziqi Chen ◽  
Bo Peng ◽  
Vassilis N. Ioannidis ◽  
Mufei Li ◽  
George Karypis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Success Rate ◽  
Similarity Search ◽  
Drug Repurposing ◽  
New Drugs ◽  
Knowledge Graph ◽  
New Treatments

Effective and successful clinical trials are essential in developing new drugs and advancing new treatments. However, clinical trials are very expensive and easy to fail. The high cost and low success rate of clinical trials motivate research on inferring knowledge from existing clinical trials in innovative ways for designing future clinical trials. In this manuscript, we present our efforts on constructing the first publicly available Clinical Trials Knowledge Graph, denoted as CTKG. CTKG includes nodes representing medical entities in clinical trials (e.g., studies, drugs and conditions), and edges representing the relations among these entities (e.g., drugs used in studies). Our embedding analysis demonstrates the potential utilities of CTKG in various applications such as drug repurposing and similarity search, among others.

scholarly journals Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Chemotherapy ◽  
2018 ◽  
Vol 63 (3) ◽  
pp. 172-180 ◽  
Author(s):  
Ivana Palucci ◽  
Giovanni Delogu
Keyword(s):  
New Drugs ◽  
Drug Resistant ◽  
Mdr Tb ◽  
Promising Area ◽  
Global Threat ◽  
New Treatments ◽  
The Cost ◽  
Length Of Therapy ◽  
Drug Resistant Strains ◽  
Combination Regimens

The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis is worsening the global threat of tuberculosis (TB). There is a need and urgency for the development of new treatments for TB, for the management of drug resistant TB (MDR-TB) and for improved regimens against drug-susceptible TB, with the goal of reducing toxicity and length of therapy that will boost patience compliance. The paucity of new drugs is a major obstacle to design new regimens while host-directed therapies (HDTs) are emerging as a promising area of research and are opening new avenues to fight TB. In this review, we discuss examples of potentially promising strategies aimed at improving the host response to M. tuberculosis, and argue how a better understanding of TB pathogenesis, with the fine characterization of the immunological mediators involved, may pave the way for the design of new therapies, the identification of new drugs or the repurposing of some already in use for other diseases. We emphasize that any HDTs shall be included as adjunct therapy to the drug-combination regimens already in use for TB, with the goal to reduce tissue damage and immunopathology and enhance bacterial clearance. We anticipate that the benefits of HDTs against TB will be highest against MDR-TB, where the activity of current regimens is poor and the cost high.

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 In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
Chemical Library ◽  
S Protein ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, more than 4.7 million people have been infected, with almost 320,000 casualties, while no vaccine nor antiviral drug is in sight. The development of a vaccine might take at least a year, and even longer for a novel drug; thus, finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a high-throughput docking approach using a novel quantum mechanical scoring for screening a chemical library of ~11,500 molecules built from FDA-approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based virtual screening, we propose several structurally diverse compounds that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

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 Novel Inhibitors of InhA Efficiently KillMycobacterium tuberculosisunder Aerobic and Anaerobic Conditions

2011 ◽  
Vol 55 (8) ◽  
pp. 3889-3898 ◽  
Author(s):  
Catherine Vilchèze ◽  
Anthony D. Baughn ◽  
JoAnn Tufariello ◽  
Lawrence W. Leung ◽  
Mack Kuo ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Acid Hydrazide ◽  
New Drugs ◽  
Type I ◽  
Drug Resistant ◽  
Anaerobic Conditions ◽  
Chemical Library

ABSTRACTDrug resistance inMycobacterium tuberculosishas become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drug-resistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibitingPlasmodium falciparumenoyl reductase, was tested againstM. tuberculosis. Four compounds were found to inhibitM. tuberculosisgrowth with MICs ranging from 1 μM to 10 μM. Testing of these compounds againstM. tuberculosis in vitrorevealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistantM. tuberculosis. These two compounds were also bactericidal againstM. tuberculosisincubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structure-activity relationship study to improve on their cytotoxicities and bactericidal activitiesin vitroandin vivo.

scholarly journals A Protocol for Identifying Potentially Repurposable Drugs Using Online Tools and Databases

2016 ◽  
Author(s):  
Aditi Chattopadhyay ◽  
Madhavi Ganapathiraju
Keyword(s):  
In Silico ◽  
Small Cell Lung Carcinoma ◽  
Drug Repurposing ◽  
Cost Effective ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
Compound Identification ◽  
Cell Lung Carcinoma ◽  
Age Related ◽  
Approved Drugs

Traditional methods for discovery and development of new drugs can be a very time-consuming and expensive process because it includes several stages such as compound identification, pre-clinical and clinical trials before the drug is approved by the US Food and Drug Administration (FDA). Therefore, drug repurposing, namely using currently FDA-approved drugs as therapeutics for other diseases than what they are originally prescribed for, is emerging to be a faster and more cost-effective alternative to current drug discovery methods. In this paper, we have described a three-step in silico protocol for analyzing transcriptomics data using online databases and bioinformatics tools for identifying potentially repurposable drugs. The efficacy of this protocol was evaluated by comparing its predictions with the findings of two case studies of recently reported repurposed drugs: HIV treating drug Zidovudine for the treatment of Dry Age-Related Macular Degeneration and the antidepressant Imipramine for Small-Cell Lung Carcinoma. The proposed protocol successfully identified the published findings, thus demonstrating the efficacy of this method. In addition, it also yielded several novel predictions that have not yet been published, including the finding that Imipramine could potentially treat Severe Acute Respiratory Syndrome (SARS), a disease that currently does not have any treatment or vaccine. Since this in-silico protocol is simple to use and does not require advanced computer skills, we believe any motivated participant with access to these databases and tools would be able to apply it to large datasets to identify other potentially repurposable drugs in the future.

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