scholarly journals A computational multi-targeting approach for drug repositioning for psoriasis treatment

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Akachukwu Ibezim ◽  
Emmanuel Onah ◽  
Ebubechukwu N. Dim ◽  
Fidele Ntie-Kang
Keyword(s):  
Anticancer Drugs ◽  
Drug Repositioning ◽  
Treatment Options ◽  
Current Treatment ◽  
Free Energies ◽  
Drug Candidates ◽  
Drug Molecules ◽  
Drug Reposition ◽  
Structural Architecture ◽  
Approved Drugs

Abstract Background Psoriasis is an autoimmune inflammatory skin disease that affects 0.5–3% of the world’s population and current treatment options are posed with limitations. The reduced risk of failure in clinical trials for repositioned drug candidates and the time and cost-effectiveness has popularized drug reposition and computational methods in the drug research community. Results The current study attempts to reposition approved drugs for the treatment of psoriasis by docking about 2000 approved drug molecules against fifteen selected and validated anti-psoriatic targets. The docking results showed that a good number of the dataset interacted favorably with the targets as most of them had − 11.00 to − 10.00 kcal/mol binding free energies across the targets. The percentage of the dataset with binding affinity higher than the co-crystallized ligands ranged from 34.76% (JAK-3) to 0.73% (Rac-1). It was observed that 12 out of the 0.73% outperformed all the co-crystallized ligands across the 15 studied proteins. All the 12 drugs identified are currently indicated as either antiviral or anticancer drugs and are of purine and pyrimidine nuclei. This is not surprising given that there is similarity in the mechanism of the mentioned diseases. Conclusion This study, therefore, suggests that; antiviral and anticancer drugs could have anti-psoriatic effects, and molecules with purine and pyrimidine structural architecture are likely templates to consider in developing anti-psoriatic agents.

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 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 Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Sangeun Jeon ◽  
Meehyun Ko ◽  
Jihye Lee ◽  
Inhee Choi ◽  
Soo Young Byun ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Drug Candidates ◽  
Global Challenge ◽  
Feasible Option ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACT Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC50s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.

scholarly journals Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

2020 ◽  
Vol 21 (12) ◽  
pp. 4270 ◽  
Author(s):  
Alfredo Juárez-Saldivar ◽  
Michael Schroeder ◽  
Sebastian Salentin ◽  
V. Joachim Haupt ◽  
Emma Saavedra ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Dihydrofolate Reductase ◽  
Drug Repositioning ◽  
Treatment Options ◽  
Ligand Interaction ◽  
Starting Point ◽  
Protein Ligand Interaction ◽  
New Treatment ◽  
Approved Drugs ◽  
Human Dihydrofolate Reductase

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4355-4379 ◽  
Author(s):  
Carolina Horta Andrade ◽  
Bruno Junior Neves ◽  
Cleber Camilo Melo-Filho ◽  
Juliana Rodrigues ◽  
Diego Cabral Silva ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Drug Repositioning ◽  
Tropical Diseases ◽  
Systematic Screening ◽  
Drug Candidates ◽  
Lead Compounds ◽  
The One ◽  
Approved Drugs

Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls.

Future and Perspectives of the Zika Virus: Drug Repurposing as a Powerful Tool for Treatment Insights

2020 ◽  
Vol 20 (18) ◽  
pp. 1917-1928
Author(s):  
Denise Rampini ◽  
Diego Campos Prieto ◽  
Ana Luisa Colzi ◽  
Renan Vinícius de Araújo ◽  
Jeanine Giarolla
Keyword(s):  
Zika Virus ◽  
Drug Repositioning ◽  
Specific Treatment ◽  
Drug Repurposing ◽  
Current Treatment ◽  
Health Concern ◽  
Drug Candidates ◽  
New Treatment ◽  
Relationship Of ◽  
Spreading Disease

The Zika virus (ZIKV) infection is a major public health concern in Brazil and worldwide, being a rapidly spreading disease with possible severe complications for pregnant women and neonates. There is currently no preventative therapy or specific treatment available. Within this context, drug repositioning is a very promising approach for the discovery of new treatment compounds, since old drugs may become new ones. Therefore, this paper aims to perform a literature mini-review to identify promising compounds to combat this virus. The mechanism of action at the molecular level and the structure-activity relationship of prototypes are discussed. Among the candidates identified, we highlight sofosbuvir, chloroquine and suramin, which present a greater quantity of experimental data to draw on for our discussion. The current treatment is palliative; therefore, this study is of paramount importance in identifying drug candidates useful for combating ZIKV.

scholarly journals New Treatment Options against Carbapenem-ResistantAcinetobacter baumanniiInfections

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Burcu Isler ◽  
Yohei Doi ◽  
Robert A. Bonomo ◽  
David L. Paterson
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
New Drugs ◽  
World Health ◽  
Content Type ◽  
Drug Candidates ◽  
Expected Benefits ◽  
New Treatment ◽  
Health Organization ◽  
Available Information

ABSTRACTCarbapenem-resistantAcinetobacter baumannii(CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.

scholarly journals Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs

2020 ◽  
Author(s):  
Sangeun Jeon ◽  
Meehyun Ko ◽  
Jihye Lee ◽  
Inhee Choi ◽  
Soo Young Byun ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Drug Candidates ◽  
Global Challenge ◽  
Feasible Option ◽  
Antiviral Activities ◽  
Approved Drugs ◽  
Near Future ◽  
Fda Approved Drugs

AbstractCOVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA-approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.

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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