scholarly journals Drug Repurposing Using Modularity Clustering in Drug-Drug Similarity Networks Based on Drug–Gene Interactions

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2117
Author(s):  
Vlad Groza ◽  
Mihai Udrescu ◽  
Alexandru Bozdog ◽  
Lucreţia Udrescu
Keyword(s):  
Interaction Network ◽  
Drug Repurposing ◽  
Gene Interaction ◽  
New Drugs ◽  
Interaction Data ◽  
Gene Interaction Network ◽  
Drug Databases ◽  
Drug Similarity

Drug repurposing is a valuable alternative to traditional drug design based on the assumption that medicines have multiple functions. Computer-based techniques use ever-growing drug databases to uncover new drug repurposing hints, which require further validation with in vitro and in vivo experiments. Indeed, such a scientific undertaking can be particularly effective in the case of rare diseases (resources for developing new drugs are scarce) and new diseases such as COVID-19 (designing new drugs require too much time). This paper introduces a new, completely automated computational drug repurposing pipeline based on drug–gene interaction data. We obtained drug–gene interaction data from an earlier version of DrugBank, built a drug–gene interaction network, and projected it as a drug–drug similarity network (DDSN). We then clustered DDSN by optimizing modularity resolution, used the ATC codes distribution within each cluster to identify potential drug repurposing candidates, and verified repurposing hints with the latest DrugBank ATC codes. Finally, using the best modularity resolution found with our method, we applied our pipeline to the latest DrugBank drug–gene interaction data to generate a comprehensive drug repurposing hint list.

scholarly journals Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and ProlixinRX (Fluphenazine) Provides Off-Label Drug Candidates

2020 ◽  
Vol 25 (10) ◽  
pp. 1123-1140
Author(s):  
Jilan Nazeam ◽  
Esraa Z. Mohammed ◽  
Mariam Raafat ◽  
Mariam Houssein ◽  
Asmaa Elkafoury ◽  
...  
Keyword(s):  
Natural Products ◽  
Evidence Synthesis ◽  
Drug Repurposing ◽  
New Drugs ◽  
Future Research ◽  
Nitrogenous Compounds ◽  
Future Research Agenda ◽  
Starting Point

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of pandemic coronavirus disease 2019 (COVID-19). So far, no approved therapy has been developed to halt the spread of the pathogen, and unfortunately, the strategies for developing a new therapy will require a long time and very extensive resources. Therefore, drug repurposing has emerged as an ideal strategy toward a smart, versatile, quick way to confine the lethal disease. In this endeavor, natural products have been an untapped source for new drugs. This review represents the confederated experience of multidisciplinary researchers of 99 articles using several databases: Google Scholar, Science Direct, MEDLINE, Web of Science, Scopus, and PubMed. To establish the hypothesis, a Bayesian perspective of a systematic review was used to outline evidence synthesis. Our docking documentation of 69 compounds and future research agenda assumptions were directed toward finding an effective and economic anti-COVID-19 treatment from natural products. Glucosinolate, flavones, and sulfated nitrogenous compounds demonstrate direct anti-SARS-CoV-2 activity through inhibition protease enzymes and may be considered potential candidates against coronavirus. These findings could be a starting point to initiate an integrative study that may encompass interested scientists and research institutes to test the hypothesis in vitro, in vivo, and in clinics after satisfying all ethical requirements.

scholarly journals Inhibitory effect of naphthoquine phosphate against Babesia gibsoni in vitro and Babesia rodhaini in vivo

2021 ◽  
Author(s):  
Shengwei Ji ◽  
Mingming Liu ◽  
Eloiza May Galon ◽  
Mohamed Abdo Rizk ◽  
Bumduuren Tuvshintulga ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Significant Inhibition ◽  
Parasite Growth ◽  
New Drugs ◽  
Control Group ◽  
Babesia Gibsoni

Abstract Background: Drug resistance and severe side effects are major challenges in the treatment of babesiosis as they lead to less choices for treatment. Development of new drugs to enrich the treatment strategies and delay the emergence of drug resistance in parasites is still needed. Naphthoquine (NQ) combined with artemisinin treats Plasmodium infection by rapid parasite clearance. The current study repurposed NQ as a babesiosis drug treatment by evaluating the effects of naphthoquine phosphate (NQP) as a single dose treatment for babesiosis. Methods: In vitro anti-Babesia activity of NQP was tested on Babesia gibsoni cultures. The inhibition of parasite growth was verified using a SYBR green I-based fluorescence assay. In vivo efficacy of NQP was evaluated using BALB/c mice infected with Babesia rodhaini. The parasitemia level and hematocrit values were monitored. Results: The half maximal inhibitory concentration of NQP against B. gibsoni in vitro was 3.3 ± 0.5 μM. Oral administration of NQP for 5 successive days at a dose of 40 mg/kg of body weight resulted in significant inhibition on parasite growth compared with the control group. All mice in NQP-treated group survived, whereas the mice in control group died between days 6 and 9 post infection. Conclusion: This is the first study to evaluate the anti-Babesia activity of NQP in vitro and in vivo. The results showed that NQP is a promising drug for babesiosis treatment and drug repurposing may provide new treatment strategies for babesiosis.

scholarly journals Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival

2021 ◽  
Vol 11 ◽  
Author(s):  
Cynthia Vanesa Rivero ◽  
Santiago José Martínez ◽  
Paul Novick ◽  
Juan Agustín Cueto ◽  
Betiana Nebaí Salassa ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Parasite Burden ◽  
Drug Repurposing ◽  
Parasite Load ◽  
New Drugs ◽  
Host Cells ◽  
Whole Body ◽  
Parasite Replication

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.

scholarly journals Striking lung cancer response to self-administration of cannabidiol: A case report and literature review

2019 ◽  
Vol 7 ◽  
pp. 2050313X1983216 ◽  
Author(s):  
Josep Sulé-Suso ◽  
Nick A Watson ◽  
Daniel G van Pittius ◽  
Apurna Jegannathen
Keyword(s):  
Lung Cancer ◽  
Cannabis Sativa ◽  
Tumour Response ◽  
Drug Repurposing ◽  
New Drugs ◽  
Self Administration ◽  
Immune Response To Cancer

In spite of new drugs, lung cancer is associated with a very poor prognosis. While targeted therapies are improving outcomes, it is not uncommon for many patients to have only a partial response, and relapse during follow-up. Thus, new drugs or re-evaluation of existing therapies used to treat other non-malignant diseases (drug repurposing) are still needed. While this research both in vitro and in vivo is being carried out, it is important to be attentive to patients where the disease responds to treatments not considered standard in clinical practice. We report here a patient with adenocarcinoma of the lung who, after declining chemotherapy and radiotherapy, presented with tumour response following self-administration of cannabidiol, a non-psychoactive compound present in Cannabis sativa. Prior work has shown that cannabidiol may have anti-neoplastic properties and enhance the immune response to cancer. The data presented here indicate that cannabidiol might have led to a striking response in a patient with lung cancer.

scholarly journals Characterization of Rheumatoid Arthritis Risk-Associated SNPs and Identification of Novel Therapeutic Sites Using an In-Silico Approach

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 501
Author(s):  
Mehran Akhtar ◽  
Yasir Ali ◽  
Zia-ul Islam ◽  
Maria Arshad ◽  
Mamoona Rauf ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Target Genes ◽  
Interaction Network ◽  
Underlying Mechanism ◽  
Nucleotide Polymorphisms ◽  
Gene Interaction Network ◽  
Rheumatoid Arthritis Risk ◽  
Novel Therapeutic

Single-nucleotide polymorphisms (SNPs) are reported to be associated with many diseases, including autoimmune diseases. In rheumatoid arthritis (RA), about 152 SNPs are reported to account for ~15% of its heritability. These SNPs may result in the alteration of gene expression and may also affect the stability of mRNA, resulting in diseased protein. Therefore, in order to predict the underlying mechanism of these SNPs and identify novel therapeutic sites for the treatment of RA, several bioinformatics tools were used. The damaging effect of 23 non-synonymous SNPs on proteins using different tools suggested four SNPs, including rs2476601 in PTPN22, rs5029941 and rs2230926 in TNFAIP3, and rs34536443 in TYK2, to be the most damaging. In total, 42 of 76 RA-associated intronic SNPs were predicted to create or abolish potential splice sites. Moreover, the analysis of 11 RA-associated UTR SNPs indicated that only one SNP, rs1128334, located in 3′UTR of ETS1, caused functional pattern changes in BRD-BOX. For the identification of novel therapeutics sites to treat RA, extensive gene–gene interaction network interactive pathways were established, with the identification of 13 potential target sites for the development of RA drugs, including three novel target genes. The anticipated effect of these findings on RA pathogenesis may be further validated in both in vivo and in vitro studies.

scholarly journals Genome-wide discovery of hidden genes mediating known drug-disease association using KDDANet

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hua Yu ◽  
Lu Lu ◽  
Ming Chen ◽  
Chen Li ◽  
Jin Zhang
Keyword(s):  
State Of The Art ◽  
Interaction Network ◽  
Drug Repurposing ◽  
Gene Interaction ◽  
Disease Association ◽  
Computational Tool ◽  
Gene Interaction Network ◽  
Disease Pathogenesis ◽  
Link Type ◽  
Genome Wide

AbstractMany of genes mediating Known Drug-Disease Association (KDDA) are escaped from experimental detection. Identifying of these genes (hidden genes) is of great significance for understanding disease pathogenesis and guiding drug repurposing. Here, we presented a novel computational tool, called KDDANet, for systematic and accurate uncovering the hidden genes mediating KDDA from the perspective of genome-wide functional gene interaction network. KDDANet demonstrated the competitive performances in both sensitivity and specificity of identifying genes in mediating KDDA in comparison to the existing state-of-the-art methods. Case studies on Alzheimer’s disease (AD) and obesity uncovered the mechanistic relevance of KDDANet predictions. Furthermore, when applied with multiple types of cancer-omics datasets, KDDANet not only recapitulated known genes mediating KDDAs related to cancer, but also revealed novel candidates that offer new biological insights. Importantly, KDDANet can be used to discover the shared genes mediating multiple KDDAs. KDDANet can be accessed at http://www.kddanet.cn and the code can be freely downloaded at https://github.com/huayu1111/KDDANet.

scholarly journals Comprehensive Analysis of Prognostic Value of MEX3A and Its Relationship with Immune Infiltrates in Ovarian Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Panpan Zhang ◽  
Tong Su ◽  
Shu Zhang
Keyword(s):  
Ovarian Cancer ◽  
Prognostic Value ◽  
Rna Binding ◽  
Interaction Network ◽  
Gene Interaction ◽  
Physical Interaction ◽  
Biological Functions ◽  
Gene Interaction Network ◽  
Immune Infiltration

MEX3A is a critical RNA-binding ubiquitin ligase that is upregulated in various types of cancer. However, the correlations of MEX3A with prognosis and its molecular mechanism in ovarian cancer (OC) remain unclear. The expression level, prognostic values, and the genetic variations of MEX3A were analyzed via Gene Expression Profiling Interactive Analysis (GEPIA) Oncomine, Kaplan–Meier plotter, and cBioPortal. We used the LinkedOmics database to investigate the functions of MEX3A coexpressed genes and performed visualizing gene interaction network analysis on the GeneMANIA website. The correlations between MEX3A and cancer immune infiltration were analyzed by the Tumor Immune Estimation Resource (TIMER) site and the TISIDB database. Furthermore, in vitro analysis was performed to evaluate the biological functions of MEX3A in OC cells. Our study showed that the expression of the MEX3A in OC was higher than in normal tissues; it had the greatest prognostic value in OC, and strong physical interaction with PABPC1, LAMTOR2, KHDRBS2, and IGF2BP2, which indicated the association between MEX3A and immune infiltration. We also found that MEX3A was negatively related to infiltrating levels of several types of immune cells, including macrophages, neutrophils, dendritic cells (DCs), B cells, and CD8+ T cells. Additionally, in vitro experiments demonstrated that MEX3A promotes proliferation and migration in OC cells. Taken together, MEX3A might influence the biological functions of OC cells by regulating the immune infiltration in the microenvironment as a prognostic biomarker and a potential therapeutic target.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals Integration of the Drug–Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts

2020 ◽  
Vol 49 (D1) ◽  
pp. D1144-D1151
Author(s):  
Sharon L Freshour ◽  
Susanna Kiwala ◽  
Kelsy C Cotto ◽  
Adam C Coffman ◽  
Joshua F McMichael ◽  
...  
Keyword(s):  
Interaction Network ◽  
Gene Interaction ◽  
Application Programming Interface ◽  
Application Framework ◽  
Interaction Data ◽  
Gene Interaction Network ◽  
Web Based ◽  
Web Resource ◽  
Interaction Database ◽  
Primary Focus

Abstract The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that provides information on drug-gene interactions and druggable genes from publications, databases, and other web-based sources. Drug, gene, and interaction data are normalized and merged into conceptual groups. The information contained in this resource is available to users through a straightforward search interface, an application programming interface (API), and TSV data downloads. DGIdb 4.0 is the latest major version release of this database. A primary focus of this update was integration with crowdsourced efforts, leveraging the Drug Target Commons for community-contributed interaction data, Wikidata to facilitate term normalization, and export to NDEx for drug-gene interaction network representations. Seven new sources have been added since the last major version release, bringing the total number of sources included to 41. Of the previously aggregated sources, 15 have been updated. DGIdb 4.0 also includes improvements to the process of drug normalization and grouping of imported sources. Other notable updates include the introduction of a more sophisticated Query Score for interaction search results, an updated Interaction Score, the inclusion of interaction directionality, and several additional improvements to search features, data releases, licensing documentation and the application framework.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

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