INTRODUCTION:

Drug repurposing, also known as drug retasking, drug reprofiling, drug rescue, drug recycling, drug redirection, and therapeutic switching, is a method of repurposing drugs. The development of novel pharmacological indications from old/existing/failed/investigational/already marketed/FDA permitted pharmaceuticals/pro-drugs, as well as the application of freshly created pharmaceuticals to illnesses other than the drug's original/intended therapeutic purpose, is detailed. It comprises finding new therapeutic applications for medications that have been approved, discontinued, abandoned, or are still in development.¹According to the National Centre for Advancing Translational Sciences (NCATS), medication repurposing is "studying medications that are currently licensed to treat one illness or condition to evaluate if they are safe and effective for treating other ailments."²

The main advantage of repurposed candidates is that they have often been shown to be sufficiently safe in preclinical models and, at the very least, early-stage human trials, making them less likely to fail later effectiveness tests due to safety concerns (unless drug–disease interactions are revealed).^3,4

Fig.1: Route map for drug repurposing. Drug repurposing starts with collection of raw data related to disease-drug-targets

(1) Followed by establishment of drug target- disease relationship (2) With an extensive support of potential evidence (3) and in silico screening techniques (4) Proof of concept is generated (5) Which is then experimentally proved (6). Further the shortlisted compounds pass through clinical trials (7) For the new indication and enter the market with FDA labelling (8 and 9). ⁵

2. Strategies for Drug Repurposing (DR):

The two DR profiles are on target and off target. In the first, the established pharmacological mechanism of a medication or drug candidate is applied to novel therapeutic indications, i.e., molecules that target the same biological target in the treatment of other diseases.⁶

· One example is the repositioning of finasteride for the treatment of male pattern baldness. This drug was originally developed to treat benign prostatic hyperplasia because its mode of action limits the bioavailability of dihydrotestosterone, a physiologically active metabolite of testosterone, the hormone responsible for normal and pathological prostate development, by blocking the 5-reductase enzyme. Finasteride reduces the bioavailability of dihydrotestosterone in the scalp, preventing hair follicle shrinking and aiding in the treatment of male pattern baldness (alopecia). An on-target profile is observed in the repositioning of finasteride, since the medication operates on the same target and provides two separate therapeutic effects.⁷

Few examples of the repurposed drugs on different backgrounds are mentioned below:

· A licensed medicine having a certain side effect that is discovered to have superior therapeutic potential for another indication through chance. For example, sildenafil, which was originally created to treat hypertension and angina pectoris, now has a sizable market for treating erectile dysfunction.⁸

· Off-label usage of medications authorized by the Food and Drug Administration (FDA). Itraconazole, which is usually used as an antifungal agent⁹, has been discovered to have an anti-angiogenesis effect. The compound's clearance through Phase 2 studies for examining its efficacy as a second line therapeutic agent in the treatment of lung cancer was guided by the discovery of the aforesaid property.¹⁰

(A) (B)

Fig 2: On target

(A) Profile where a known pharmacological mechanism of a drug or drug candidate is applied to new therapeutic indications and off target (B) Profile where the pharmacological mechanism is unknown and the drugs act on new targets, out of the original scope, for new therapeutic indications.

2. Advantages and Challenges:

Repurposing has a number of advantages over traditional drug development processes. A relocated pharmaceutical does not require the six to nine years typically required for new medication development, instead proceeding directly to preclinical testing and clinical trials, reducing risk and cost. The risks associated with early-stage development failures, which are considerable in traditional techniques, are reduced, as well as considerable cost savings and a potential boost in clinical safety.¹¹

Fig 3: Traditional drug discovery vs. drug repurposing.

· The DR, however, faces significant challenges: fresh preclinical and/or clinical studies may be required if the existing data is insufficient, obsolete, or does not fulfill the standards of regulatory organizations such as ANVISA, FDA, or the European Medicines Agency (EMA). Combinations of two or more medications with diverse mechanisms of action are an option that can aid in the effectiveness of DR.^12,13

· DR is complicated by governmental and intellectual property/patent hurdles. In the United States, for example, where a medical product's patent is valid for up to 20 years, only the patent owner has the authority to update or insert any data in the leaflet, repositioning the medicine while the patent is active. ^14,15

· Pharmaceutical are widely available to various manufacturers, registering a patent source for a repositioning that includes generic pharmaceuticals does not ensure a term of market exclusivity.¹⁶

· Concept Therapeutics, which specializes in repositioning, repositioned mifepristone for the treatment of hyperglycemia related to hypercortisolism.¹⁷

3. Approaches of Drug Repurposing:

The experiment-based and in silico-based approaches to medication repositioning are two distinct but are complementary approaches. The activity-based repositioning methodology, also known as experiment-based repositioning, refers to the use of experimental assays to evaluate existing drugs for new pharmacological indications. It comprises protein target-based and cell/organism-based screening in in-vitro and/or in-vivo disease models without knowing the structure of the target protein.^18,19In silico repositioning, on the other hand, uses computational biology and bioinformatics/cheminformatics tools to perform virtual screening of public databases of large drug/chemical libraries, which is based on the molecular interaction between the therapeutic molecule and the protein target.²⁰

The differences between activity- and in silico-based approaches of drug repositioning are summarized in Table1.^{21, 22}

Activity-based approach	In silico -based approach
● Experimental (in vitro and in vivo) screening	● Computational (virtual) screening
● Target-based and cell/organism-based screening Assay	● Protein target-based screening
● Requires no structural information of target proteins and drug-induced cell/disease phenotypic information	● Requires structural information of target proteins and drug-induced cell/disease phenotypic information
● Time and labor consuming	● Time and labor efficient
● Lower rate of false positive hits during the screening	● Higher rate of false positive hits during the screening

Figure represents the approaches of drug repositioning.

Fig 4: Approaches of drug repositioning.

In recent years, discovery scientists and researchers have used in silico and experimental approaches to investigate novel therapeutic indications for existing drugs. This strategy is both credible and dependable.²³

4. Drug Repurposing Opportunities:

4.1. Rare and neglected conditions:

For rare and neglected diseases, where the economics of generating a drug are unfavorable, drug repurposing is particularly enticing, which explains why academics and non-profit organizations play such a big role in the drug discovery process for those diseases, as well as why specialized regulatory measures and public policies support research into these disorders. Such measures include tax exemptions, fast-track approval, grants, and regulatory fee exemptions.^24,25

4.2. Precision medicine:

Precision medicine is a new approach to medicine that takes into account individual differences in genes, environment, and lifestyle when deciding on or pursuing a treatment for a given person. It is becoming increasingly obvious that several disorders with common qualities that were once thought to be a single disease are actually a spectrum of diseases, and that more effective and safe treatments may be developed if they were tailored to variances in an individual's genome, transcriptome, proteome, and metabolome, or to specific types of a general ailment.^26,27

4.3. Systems medicine:

Previous paradigms in drug development: phenotypic-oriented and target-oriented, ‘rational' drug discovery are both addressed by systems medicine/network pharmacology. Network and metabolic control analyses can be helpful in the development of multi-target treatments or the selection of a synergistic medication combination.

Synergistic medication combinations are an option to monotherapies for increasing the success rate of drug repositioning since they can reduce the required therapeutic doses.²⁸

4.4. Collaborative models:

Pharmaceutical companies have access to highly valuable chemical libraries of unsuccessful or shelved drug ideas, as well as firsthand knowledge of translational research and clinical development. They can also provide access to screening technologies that are difficult for most academic institutions to get and maintain.²⁹

5. Methodologies of Drug Repurposing:

The methodologies applied in repositioning can be divided into three groups:

(i) Drug-oriented

(ii) Target-oriented

(iii) Disease/therapy-oriented

The number and quality of pharmacological, toxicological, and biological data determine the type of guidance in which the techniques are used.³⁰

· The structural features of the molecules, off-label use data, adverse effects, and phenotypic screening are all assessed in drug-oriented methodologies. This screening is a method of identifying molecules having biological effects in cell/animal assays in order to find chemicals that produce a desired phenotypic change.^31,32To date, the largest DR achievements have been achieved with this orientation profile.³³

· In-vitro and in-vivo high-throughput and/or high-content screening of pharmaceuticals for a protein or biomarker of interest, as well as in silico screening of pharmaceuticals or compounds from drug libraries, such as ligand-based screening or docking, are examples of target-based DR approaches.³⁴ Because most targets are linked directly to disease mechanisms, targeted-based methods considerably boost the chances of drug discovery as compared to drug-oriented strategies.

· Proteomics, genomics, metabolomics, or data on how medications modulate phenotypes in disorders, such as knowledge of adverse and side effects with suspected off-target processes, provide this information. Computational approaches, such as network and route analysis, are used extensively.^35,36

A detailed enumeration of various methodologies employed in drug repositioning along with suitable examples is given in Table.^37,38

Methodology	Type of method, category	Method/specific approach	Example (s)
Drug-oriented
Phenotypic screening	Blinded/ Target-based, Screening	In vitro and in vivo HTS/HCS screening	Sildenafil (erectile dysfunction), rituximab (breast cancer)
Target 3D structure, chemical structure, information of drugs and ligands	Target-based, Cheminformatics	In silico screening, ligand-based screening and molecular docking fragment-based screening	Fluorouracil (lung cancer), etoposide (bladder cancer)
Drug-target information, chemical structure, information of targets and drugs	Knowledge-based, Bioinformatics/ Chemoinformatics	Drug–target prediction	Simvastatin, ketoconazole (breast cancer
Disease-oriented
Available Pathway information	Knowledge-based, Bioinformatics	Discovery of disease mechanism and address of key targets	Vismodegib (skin cancer)
Disease omics data, available pathway information, and protein interaction network	Pathway or network- based, Network biology	Analysis of disease-specific pathways and networks to identify key targets	Sunitinib, dasatinib (breast cancer, brain tumor)
Therapy-oriented
Drug omics data	Signature- based or Signature- and network- based, Bioinformatics and/or Network biology	Studying gene signatures	Sirolimus (acute lymphoblastic leukemia), Fasudil (neurodegenerative disorders)
Drug omics data, disease pathway and protein interaction network	Targeted- mechanism based, Network biology and Systems biology	Elucidating targeted pathways	Daunorubicin, clomifene (breast cancer)

5. Current challenges and prospects for repurposing activities in pharmaceutical companies:

Pharmaceutical companies encounter a wide range of challenges when it comes to drug repurposing. In addition to the scientific hurdles of identifying promising and stable candidate compounds, financial strategies must be developed to facilitate the commercialization of existing molecules as medicines for new indications. Despite the possibility for a shortened clinical development path for repurposed medications, there is still a considerable commitment in the requirement to demonstrate efficacy of the molecules in new indications, and pharmaceutical companies have a challenge in trying to recoup the investment required to bring a repurposed product to market.³⁹

Some examples of Repurposed Drugs:

Table 1: Repurposed drugs for several indications

Drug	Usual usage	Repurposed to treat
Metformin	Anti-diabetic Pancreatic	cancer stem cell
Tamoxifen	Breast cancer	Anti-bacterial Activity
Nilotinib	Leukaemia	Parkinson’s Disease
Raloxifene	Breast cancer	Osteoporosis
Liraglutide	Anti-diabetic	Liver disease, weight loss
Amantadine	Anti-viral	Parkinson’s disease
Aspirin	Pain killer	Heart attack
Thalidomide	Sedative	Leprosy
Zidovudine	HIV/AIDS	Cancer
Ibuprofen	Anti inflammatory	Anti-microbial
Cyclosporine	Rheumatoid arthritis and Psoriasis	Transplant rejection

Table 2: Repurposed drugs for bacterial infections⁴⁰

Drug	Usual usage	Repurposed to treat
Chlorpromazine	Dopamine antagonist to treat schizophrenia	Anti-amoebic, anti-bacterial Agents
Phenothiazine prototype Methdilazine	Skin allergy	Anti-bacterial agents
Trifluoperazine Phenothiazine	Dopamine antagonist to treat schizophrenia	Anti-bacterial agents
Oxyfedrine hydrochloride	Used in the treatment of cardiovascular disorders like angina pectoris as vasodilators	Anti-bacterial agents
Amlodipine	Anti-hypertensive agent’s	Anti-bacterial, Antileishmanial and Antitrypanosomial
Dicyclomine	Anti-spasmodic agent	Anti-bacterial agents
Ebselen	Anti-atherosclerotic, Anti-inflammatory and Anti-oxidative	Anti-microbial activity
Gallium	Used to treat syphilis in rabbits and trypanosomiasis in mice	Anti-bacterial agents
Ciclopirox	Anti-fungal	Bacteriostatic and bactericide Activity

Table 3: Repurposed drugs for cancer treatment^41,42

Drug	Usual usage	Repurposed to treat
Metformin	Diabetes	Breast Cancer
Mebendazole	Anti-helminthic	Lung Cancer
Aspirin	Stroke	Colorectal Cancer
Chloroquine	Anti-malarial	Suppress growth of tumour cells
Raloxifene	Osteoporosis	Breast Cancer
Thalidomide	Nausea	Bone marrow cancer
Cimetidine	Gastric or duodenal ulcer	Colorectal cancer

6. CONCLUSION:

In this context, the concept of repurposing a drug opens up a lot of possibilities for discovering the medicine's hidden potential and recycling it. Although researchers in this period are privileged to have access to such computational methods, there is still a gap to be addressed in terms of addressing post-prediction flaws in optimizing dosage regimens, formulation, and target population selection, among other things.

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Received on 29.06.2021 Modified on 30.10.2021

Research J. Pharm. and Tech 2022; 15(9):4309-4314.

DOI: 10.52711/0974-360X.2022.00723