scholarly journals Integrating gene expression and clinical data to identify drug repurposing candidates for hyperlipidemia and hypertension

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Patrick Wu ◽  
QiPing Feng ◽  
Vern Eric Kerchberger ◽  
Scott D. Nelson ◽  
Qingxia Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Development ◽  
Clinical Data ◽  
High Throughput ◽  
Research Program ◽  
Human Gene ◽  
Drug Repurposing ◽  
Therapeutic Effects ◽  
New Drug Development ◽  
Approved Drugs

AbstractDiscovering novel uses for existing drugs, through drug repurposing, can reduce the time, costs, and risk of failure associated with new drug development. However, prioritizing drug repurposing candidates for downstream studies remains challenging. Here, we present a high-throughput approach to identify and validate drug repurposing candidates. This approach integrates human gene expression, drug perturbation, and clinical data from publicly available resources. We apply this approach to find drug repurposing candidates for two diseases, hyperlipidemia and hypertension. We screen >21,000 compounds and replicate ten approved drugs. We also identify 25 (seven for hyperlipidemia, eighteen for hypertension) drugs approved for other indications with therapeutic effects on clinically relevant biomarkers. For five of these drugs, the therapeutic effects are replicated in the All of Us Research Program database. We anticipate our approach will enable researchers to integrate multiple publicly available datasets to identify high priority drug repurposing opportunities for human diseases.

scholarly journals Discovery Methodology of Novel Conotoxins from Conus Species

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 417 ◽  
Author(s):  
Ying Fu ◽  
Cheng Li ◽  
Shuai Dong ◽  
Yong Wu ◽  
Dongting Zhangsun ◽  
...  
Keyword(s):  
Drug Development ◽  
Gene Cloning ◽  
High Throughput ◽  
Disulfide Bond ◽  
Cone Snail ◽  
Crude Venom ◽  
Drug Candidates ◽  
Conus Species ◽  
New Drug Development ◽  
Natural Peptides

Cone snail venoms provide an ideal resource for neuropharmacological tools and drug candidates discovery, which have become a research hotspot in neuroscience and new drug development. More than 1,000,000 natural peptides are produced by cone snails, but less than 0.1% of the estimated conotoxins has been characterized to date. Hence, the discovery of novel conotoxins from the huge conotoxin resources with high-throughput and sensitive methods becomes a crucial key for the conotoxin-based drug development. In this review, we introduce the discovery methodology of new conotoxins from various Conus species. It focuses on obtaining full N- to C-terminal sequences, regardless of disulfide bond connectivity through crude venom purification, conotoxin precusor gene cloning, venom duct transcriptomics, venom proteomics and multi-omic methods. The protocols, advantages, disadvantages, and developments of different approaches during the last decade are summarized and the promising prospects are discussed as well.

Genomics and Systems Biology.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-51-sci-51
Author(s):  
Todd R. Golub
Keyword(s):  
Gene Expression ◽  
High Throughput ◽  
Biological Networks ◽  
High Throughput Screening ◽  
Expression Profiles ◽  
Low Cost ◽  
Gene Expression Profiles ◽  
Gene Expression Signature ◽  
Small Molecule Libraries ◽  
Approved Drugs

Genomics holds particular potential for the elucidation of biological networks that underlie disease. For example, gene expression profiles have been used to classify human cancers, and have more recently been used to predict graft rejection following organ transplantation. Such signatures thus hold promise both as diagnostic approaches and as tools with which to dissect biological mechanism. Such systems-based approaches are also beginning to impact the drug discovery process. For example, it is now feasible to measure gene expression signatures at low cost and high throughput, thereby allowing for the screening libraries of small molecule libraries in order to identify compounds capable of perturbing a signature of interest (even if the critical drivers of that signature are not yet known). This approach, known as Gene Expression-Based High Throughput Screening (GE-HTS), has been shown to identify candidate therapeutic approaches in AML, Ewing sarcoma, and neuroblastoma, and has identified tool compounds capable of inhibiting PDGF receptor signaling. A related approach, known as the Connectivity Map (www.broad.mit.edu/cmap) attempts to use gene expression profiles as a universal language with which to connect cellular states, gene product function, and drug action. In this manner, a gene expression signature of interest is used to computationally query a database of gene expression profiles of cells systematically treated with a large number of compounds (e.g., all off-patent FDA-approved drugs), thereby identifying potential new applications for existing drugs. Such systems level approaches thus seek chemical modulators of cellular states, even when the molecular basis of such altered states is unknown.

scholarly journals Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients

2021 ◽  
Author(s):  
Hong Wang ◽  
Jingqing Zhang ◽  
Zhigang Lu ◽  
Weina Dai ◽  
Chuanjiang Ma ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Protein Protein Interaction ◽  
Disease Module ◽  
Approved Drugs ◽  
Data Driven Modeling ◽  
The Relationship

Abstract After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein–protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

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 Virtual High Throughput Screening Based Prediction of Potential Drugs for COVID-19

2020 ◽  
Author(s):  
Sekhar Talluri
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Viral Infections ◽  
Genomic Sequence ◽  
Reproduction Number ◽  
Three Dimensional ◽  
Drug Repurposing ◽  
Dimensional Structure ◽  
Main Protease ◽  
Approved Drugs

SARS-CoV-2 is a betacoronavirus that was first identified during the Wuhan COVID-19 epidemic in 2019. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using virtual high throughput screening. The results of this study confirm earlier preliminary reports based on studies of homologs that some of the drugs approved for treatment of other viral infections also have the potential for treatment of COVID-19. Approved anti-viral drugs that target proteases were ranked for potential effectiveness against COVID-19 and novel candidates for drug repurposing were identified.

High-Throughput Transcriptome Analysis Reveals Therapeutic Effects of Statin on Alternations of Cardiac Gene Expression in Heart Failure

2016 ◽  
Vol 22 (9) ◽  
pp. S167
Author(s):  
Atsuyuki Wada ◽  
Takehiro Matsumoto ◽  
Atsushi Taniguchi ◽  
Masanori Fujii ◽  
Masataka Hara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
High Throughput ◽  
Transcriptome Analysis ◽  
Therapeutic Effects ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

scholarly journals A new computational drug repurposing method using established disease–drug pair knowledge

2019 ◽  
Vol 35 (19) ◽  
pp. 3672-3678 ◽  
Author(s):  
Nafiseh Saberian ◽  
Azam Peyvandipour ◽  
Michele Donato ◽  
Sahar Ansari ◽  
Sorin Draghici
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Large Scale ◽  
Expression Profiles ◽  
Drug Repurposing ◽  
Supervised Machine Learning ◽  
Supplementary Information ◽  
Sources Of Information ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Motivation Drug repurposing is a potential alternative to the classical drug discovery pipeline. Repurposing involves finding novel indications for already approved drugs. In this work, we present a novel machine learning-based method for drug repurposing. This method explores the anti-similarity between drugs and a disease to uncover new uses for the drugs. More specifically, our proposed method takes into account three sources of information: (i) large-scale gene expression profiles corresponding to human cell lines treated with small molecules, (ii) gene expression profile of a human disease and (iii) the known relationship between Food and Drug Administration (FDA)-approved drugs and diseases. Using these data, our proposed method learns a similarity metric through a supervised machine learning-based algorithm such that a disease and its associated FDA-approved drugs have smaller distance than the other disease-drug pairs. Results We validated our framework by showing that the proposed method incorporating distance metric learning technique can retrieve FDA-approved drugs for their approved indications. Once validated, we used our approach to identify a few strong candidates for repurposing. Availability and implementation The R scripts are available on demand from the authors. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications againstStaphylococcus aureusSmall-Colony Variants

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Ryan P. Trombetta ◽  
Paul M. Dunman ◽  
Edward M. Schwarz ◽  
Stephen L. Kates ◽  
Hani A. Awad
Keyword(s):  
High Throughput ◽  
Bactericidal Activity ◽  
High Throughput Screening ◽  
Drug Repurposing ◽  
Growth Patterns ◽  
Content Type ◽  
Airway Infections ◽  
Approved Drugs ◽  
Conventional Antibiotics ◽  
Fda Approved Drugs

ABSTRACTDrug repurposing offers an expedited and economical route to develop new clinical therapeutics in comparison to traditional drug development. Growth-based high-throughput screening is concomitant with drug repurposing and enables rapid identification of new therapeutic uses for investigated drugs; however, this traditional method is not compatible with microorganisms with abnormal growth patterns such asStaphylococcus aureussmall-colony variants (SCV). SCV subpopulations are auxotrophic for key compounds in biosynthetic pathways, which result in low growth rate. SCV formation is also associated with reduced antibiotic susceptibility, and the SCV’s ability to revert to the normal cell growth state is thought to contribute to recurrence ofS. aureusinfections. Thus, there is a critical need to identify antimicrobial agents that are potent against SCV in order to effectively treat chronic infections. Accordingly, here we describe adapting an adenylate kinase (AK)-based cell death reporter assay to identify members of a Food and Drug Administration (FDA)-approved drug library that display bactericidal activity againstS. aureusSCV. Four library members, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, exhibited potent SCV bactericidal activity against a stableS. aureusSCV. Further investigation showed that sitafloxacin was potent against methicillin-susceptible and -resistantS. aureus, as well asS. aureuswithin an established biofilm. Taken together, these results demonstrate the ability to use the AK assay to screen small-molecule libraries for SCV bactericidal agents and highlight the therapeutic potential of sitafloxacin to be repurposed to treat chronicS. aureusinfections associated with SCV and/or biofilm growth states.IMPORTANCEConventional antibiotics fail to successfully treat chronic osteomyelitis, endocarditis, and device-related and airway infections. These recurring infections are associated with the emergence of SCV, which are recalcitrant to conventional antibiotics. Studies have investigated antibiotic therapies to treat SCV-related infections but have had little success, emphasizing the need to identify novel antimicrobial drugs. However, drug discovery is a costly and time-consuming process. An alternative strategy is drug repurposing, which could identify FDA-approved and well-characterized drugs that could have off-label utility in treating SCV. In this study, we adapted a high-throughput AK-based assay to identify 4 FDA-approved drugs, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, which display antimicrobial activity againstS. aureusSCV, suggesting an avenue for drug repurposing in order to effectively treat SCV-related infections. Additionally, this screening paradigm can easily be adapted for other drug/chemical libraries to identify compounds bactericidal against SCV.

scholarly journals Identifying SARS-CoV-2 entry inhibitors through drug repurposing screens of SARS-S and MERS-S pseudotyped particles

2020 ◽  
Author(s):  
Catherine Z. Chen ◽  
Miao Xu ◽  
Manisha Pradhan ◽  
Kirill Gorshkov ◽  
Jennifer Petersen ◽  
...  
Keyword(s):  
High Throughput ◽  
Broad Spectrum ◽  
Vaccine Development ◽  
Drug Repurposing ◽  
Cell Entry ◽  
Entry Inhibitors ◽  
Small Molecule Drugs ◽  
Global Pandemic ◽  
Initial Stage ◽  
Approved Drugs

AbstractWhile vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high throughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle entry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry. This work should contribute to the development of effective treatments against the initial stage of viral infection, thus reducing viral burden in COVID-19 patients.Abstract Figure

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