Gene Signature-Based Drug Repositioning

With the advent of dynamical omics technology, especially the transcriptome and proteome, a huge amount of data related to various diseases and approved drugs are available under multi global projects or researches with their interests. These omics data and new machine learning technology largely promote the translation of drug research into clinical trials. We will cover the following topics in this chapter. 1) An introduction to the basic discipline of gene signature-based drug repurposing; 2) databases of genes, drugs and diseases; 3) gene signature databases of the approved drugs; 4) gene signature databases of various diseases; 5) gene signature-based methods and tools for drug repositioning; 6) new omics technology for drug repositioning; 7) drug repositioning examples with reproducible code. And finally, discuss the future trends and conclude.

Download Full-text

Drug REpurposing using AI/ML tools - for Rare Diseases (DREAM-RD): A case study with Fragile X Syndrome (FXS)

10.1101/2020.09.25.311142 ◽

2020 ◽

Author(s):

Kavitha Agastheeswaramoorthy ◽

Aarti Sevilimedu

Keyword(s):

Fragile X Syndrome ◽

Drug Repositioning ◽

Fragile X ◽

Drug Repurposing ◽

Machine Learning Algorithms ◽

Specific Gene ◽

Drug Induced ◽

Approved Drugs ◽

Disease Specific

AbstractDrug repositioning is emerging as an increasingly relevant option for rare disease therapy and management. Various methods for identifying suitable drug candidates have been tried and range from clinical symptomatic repurposing to data driven strategies which are based on the disease-specific gene or protein expression, modification, signalling and physiological perturbation profiles. The use of Artificial Intelligence (AI) and machine learning algorithms (ML) allows one to combine diverse data sets, and extract disease-specific data profiles which may not be intuitive or apparent from a subset of data. In this case study with Fragile X syndrome and autism, we have used multiple computational methodologies to extract profiles, which are then combined to arrive at a comprehensive signature (disease DEG). This DEG was then used to interrogate the large collection of drug-induced perturbation profiles present in public databases, to find appropriate small molecules to reverse or mimic the disease-profiles. We have labelled this pipeline Drug Repurposing using AI/ML tools - for Rare Diseases (DREAM-RD). We have shortlisted over 100 FDA approved drugs using the aforementioned pipeline, which may potentially be useful to ameliorate autistic phenotypes associated with FXS.

Download Full-text

Computational guided approach for drug repurposing against SARS-CoV-2

Future Virology ◽

10.2217/fvl-2020-0403 ◽

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.

Download Full-text

Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium

PLoS ONE ◽

10.1371/journal.pone.0257784 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257784

Author(s):

Rajaneesh K. Gupta ◽

Enyinna L. Nwachuku ◽

Benjamin E. Zusman ◽

Ruchira M. Jha ◽

Ava M. Puccio

Keyword(s):

Gene Networks ◽

Drug Targets ◽

Drug Repositioning ◽

Meta Analysis ◽

Drug Repurposing ◽

Gene Signature ◽

Airway Epithelial Cells ◽

Gene Ranking ◽

Human Airway ◽

Ranking Algorithms

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.

Download Full-text

Drug Repurposing: A Review

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i31b31704 ◽

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.

Download Full-text

Harnessing Drug Repurposing for Exploration of New Diseases: An Insight to Strategies and Case Studies

Current Molecular Medicine ◽

10.2174/1566524020666200619125404 ◽

2020 ◽

Vol 20 ◽

Author(s):

Priti Jain ◽

Shreyans K Jain ◽

Munendra Jain

Keyword(s):

Drug Discovery ◽

Case Studies ◽

Drug Repositioning ◽

Pediatric Population ◽

Clinical Status ◽

Drug Repurposing ◽

Discovery Research ◽

Drug Discovery Research ◽

Traditional Drug ◽

Approved Drugs

Background: Traditional drug discovery is time consuming, costly, and risky process. Owing to the large investment, excessive attrition, and declined output; drug repurposing has become a blooming approach for the identification and development of new therapeutics. The method has gained momentum in the past few years and has resulted in many excellent discoveries. Industries are resurrecting the failed and shelved drugs to save time and cost. The process accounts for approximately 30% of the new US Food and Drug Administration approved drugs and vaccines in recent years. Methods: A systematic literature search using appropriate keywords were made to identify articles discussing the different strategies being adopted for repurposing and various drugs that have been/are being repurposed. Results: This review aims to describe the comprehensive data about the various strategies (Blinded search, computational approaches, and experimental approaches) used for the repurposing along with success case studies (treatment for orphan diseases, neglected tropical disease, neurodegenerative diseases, and drugs for pediatric population). It also inculcates an elaborated list of more than 100 drugs that have been repositioned, approaches adopted, and their present clinical status. We have also attempted to incorporate the different databases used for computational repurposing. Conclusion: The data presented is proof that drug repurposing is a prolific approach circumventing the issues poised by conventional drug discovery approaches. It is a highly promising approach and when combined with sophisticated computational tools it also carries high precision. The review would help researches in prioritizing the drug-repositioning method much needed to flourish the drug discovery research.

Download Full-text

Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19

10.1101/2020.06.16.153403 ◽

2020 ◽

Cited By ~ 3

Author(s):

Malina A. Bakowski ◽

Nathan Beutler ◽

Emily Chen ◽

Tu-Trinh H. Nguyen ◽

Melanie G. Kirkpatrick ◽

...

Keyword(s):

Drug Repositioning ◽

Drug Repurposing ◽

Oral Drug ◽

Therapeutic Drug ◽

The Novel ◽

High Content Imaging ◽

Drug Candidates ◽

Polymerase Inhibitor ◽

Approved Drugs

AbstractThe ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.

Download Full-text

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

International Journal of Molecular Sciences ◽

10.3390/ijms21144957 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4957 ◽

Cited By ~ 1

Author(s):

Federica Laudisi ◽

Martin Marônek ◽

Antonio Di Grazia ◽

Giovanni Monteleone ◽

Carmine Stolfi

Keyword(s):

Digestive System ◽

Drug Repositioning ◽

Drug Repurposing ◽

The Body ◽

Attrition Rates ◽

Anti Cancer ◽

Approved Drugs ◽

Parasitic Worms ◽

Effective Drugs ◽

Anthelmintic Drugs

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.

Download Full-text

Drug Repurposing of potential drug targets for treatment of COVID-19

10.1101/2021.06.02.21258223 ◽

2021 ◽

Author(s):

Rajaneesh Gupta ◽

Enyinna Nwachuku ◽

Benjamin Zusman ◽

Ruchira Jha ◽

Ava Puccio

Keyword(s):

Gene Networks ◽

Drug Targets ◽

Drug Repositioning ◽

Meta Analysis ◽

Drug Repurposing ◽

Gene Signature ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Gene Ranking ◽

Ranking Algorithms

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic-COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature'-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.

Download Full-text

Drug Repurposing and Orphan Disease Therapeutics

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications ◽

10.5772/intechopen.91941 ◽

2020 ◽

Author(s):

Neha Dhir ◽

Ashish Jain ◽

Dhruv Mahendru ◽

Ajay Prakash ◽

Bikash Medhi

Keyword(s):

Drug Repositioning ◽

Low Cost ◽

Drug Repurposing ◽

Orphan Disease ◽

Current Status ◽

Regulatory Guidelines ◽

Repurposed Drugs ◽

Approved Drugs ◽

Clinical Conditions ◽

Fda Approved Drugs

Drug repurposing (or drug repositioning) is an innovative way to find out the new indications of a drug that already exists in the market with known therapeutic indications. It offers an effective way to drug developers or the pharmaceutical companies to identify new targets for FDA-approved drugs. Less time consumption, low cost and low risk of failure are some of the advantages being offered with drug repurposing. Sildenafil (Viagra), a landmark example of a repurposed drug, was introduced into the market as an antianginal drug. But at present, its use is repurposed as drug for erectile dysfunction. In a similar way, numerous drugs are there that have been successfully repurposed in managing the clinical conditions. The chapter would be highlighting the various drug repurposing strategies, drugs repurposed in the past and the current status of repurposed drugs in the orphan disease therapeutics along with regulatory guidelines for drug repurposing.

Download Full-text

Chemical and Textual Embeddings for Drug Repurposing

Proceedings of the AAAI Conference on Artificial Intelligence ◽

10.1609/aaai.v34i08.7046 ◽

2020 ◽

Vol 34 (08) ◽

pp. 13338-13343

Author(s):

Galia Nordon ◽

Levi Gottlieb ◽

Kira Radinsky

Keyword(s):

Drug Repositioning ◽

Drug Repurposing ◽

Drug Approval ◽

Major Health ◽

Embedding Technique ◽

Alternative Techniques ◽

Approved Drugs ◽

Chemical Groups ◽

Novel Drug ◽

Expensive Process

Drug approval is a long and expensive process, that can take 10-15 years and more than 2 billion dollars. Therefore alternative techniques, such as drug repositioning, to identify new uses for approved drugs, has been gaining increasing attention. We examine the employment of different drug embeddings to predict successful drug repositioning. We study the employment of drug molecular structure and show that using larger chemical construct, such as large functional chemical groups, is much more effective than small sub-structures. We then study embeddings that are based on textual medical publications and compare them with the chemical-structure-based embeddings. We eventually present a novel embedding technique to combine the merit of the textual and chemical-based approaches. We provide empirical results on a repositioning benchmark set. Additionally, we present an application of such embedding as part of an ongoing repositioning research conducted with a major health care supplier, and identify a novel drug and indication. The pair has been verified on a corpus of 1.5 million patient EHR data.

Download Full-text