Drug repurposing (DR) (also known as drug repositioning) is a process of identifying new therapeutic use(s) for old/existing/available drugs. It is an effective strategy in discovering or developing drug molecules with new pharmacological/therapeutic indications. In recent years, many pharmaceutical companies are developing new drugs with the discovery of novel biological targets by applying the drug repositioning strategy in drug discovery and development program. This strategy is highly efficient, time saving, low-cost and minimum risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. Thus, drug repositioning is an effective alternative approach to traditional drug discovery process. Finding new molecular entities (NME) by traditional or de novo approach of drug discovery is a lengthy, time consuming and expensive venture. Drug repositioning utilizes the combined efforts of activity-based or experimental and in silico-based or computational approaches to develop/identify the new uses of drug molecules on a rational basis. It is, therefore, believed to be an emerging strategy where existing medicines, having already been tested safe in humans, are redirected based on a valid target molecule to combat particularly, rare, difficult-to-treat diseases and neglected diseases.
- drug repurposing
- drug discovery
- in silico repositioning
- activity-based repositioning
- target-based screening
- therapeutic indication
Drug repurposing (DR) is also known as drug repositioning, drug re-tasking, drug reprofiling, drug rescuing, drug recycling, drug redirection, and therapeutic switching. It can be defined as a process of identification of new pharmacological indications from old/existing/failed/investigational/already marketed/FDA approved drugs/pro-drugs, and the application of the newly developed drugs to the treatment of diseases other than the drug’s original/intended therapeutic use. It involves establishing new therapeutic uses for already known drugs, including approved, discontinued, abandoned and experimental drugs [1, 2, 3]. Traditional drug discovery is a time-consuming, laborious, highly expensive and high risk process. The novel approach of drug repositioning has the potential to be employed over traditional drug discovery program by mitigating the high monetary cost, longer duration of development and increased risk of failure. It confers reduced risk of failure where a failure rate of ~45% is associated due to safety or toxicity issues in traditional drug discovery program with additional benefit of saving up to 5–7 years in average drug development time [4, 5]. In recent years, the drug repositioning strategy has gained considerable momentum with about one-third of the new drug approvals correspond to repurposed drugs which currently generate around 25% of the annual revenue for the pharmaceutical industry . It has been accounted that approximately 30% of the US Food and Drug Administration (FDA) approved drugs and biologics (vaccines) are repositioned drugs. According to recent estimates, pharmaceutical industries have significantly placed the market for repurposed drugs at $24.4 billion in 2015 with projected growth up to $31.3 billion in 2020. The first example of drug repositioning was an accidental discovery/serendipitous observations in the 1920s. After about a century of development, more approaches were developed for accelerating the process of drug repositioning. Some most successful and best-known drugs that have been emerged out of the DR approach are sildenafil, minoxidil, aspirin, valproic acid, methotrexate etc. . For example, sildenafil originally developed for the treatment of hypertension and angina pectoris has currently been used to treat erectile dysfunction.
2. Traditional drug discovery vs. drug repurposing
The traditional approach to drug discovery involves
However, the repositioning strategy of using approved therapeutics for new therapeutic indications has demonstrated success particularly through prior serendipitous observations. The discovery of drugs by this approach is certainly advantageous as depicted above over traditional drug discovery program as described below. For example, sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor initially developed for coronary artery disease (angina) by Pfizer (1985) has been repurposed for the treatment of erectile dysfunction. It potentially reduced the development cost at shorter development time. Metformin (Glucophage), an oral anti-diabetic medication used widely in type 2 diabetes mellitus has been developed as a cancer therapeutic which is currently under phase II/phase III clinical trials [1, 12].
Drug repositioning has several advantages in comparison with traditional approaches to drug discovery. When comparing with traditional drug discovery program, a significant reduction of the time spent in R&D can be observed. In traditional approach, it is estimated that 10–16 years are spent for the development of a new drug, while in DR the estimated time is between 3 and 12 years. It only costs $1.6 billion to develop a new drug using a drug repositioning strategy, while the drug development through traditional strategy costs around $12 billion. Moreover, researchers only need 1–2 years to identify new drug targets and about an average of 8 years to develop a repositioned drug [6, 7]. A repositioned drug does not require the initial 6–9 years typically required for the development of new drugs by traditional process, but instead enters directly to preclinical testing and clinical trials, thus reducing the overall risk, time and cost of development. Reports suggest that repurposed drugs require approximately 3–12 years for gaining approval from FDA and/or European Medicines Agency (EMA) and at reduced 50–60% cost. At the beginning of a repositioning project, a range of pre-clinical (pharmacological, toxicological, etc.), and clinical efficacy and safety information is already available, as the candidate drug has already undergone through the early stages of drug development such as structural optimization, preclinical and/or clinical trials, in addition to the possibility of the candidate drug being an approved drug, having its clinical efficacy and safety profile. In this way, there is a reduction of the risks associated with failures in the early stages of development, which are high in traditional approaches, as well as a significant reduction of cost with the possible increase in clinical safety and therefore, high success rate [13, 14].
Due to the availability of previously collected pharmacokinetic, toxicological, clinical and safety data at the start of a repurposing development project, the advantages that are encountered with drug repurposing over traditional drug discovery approach are reduced time of development, lower cost of development and reduced risks of failure in the clinical development.
It has been estimated that the time required for development of a repositioned drug varies from 3 to 12 years (which is about 10–17 years in traditional discovery program) with substantially lower costs, which ensures the repositioning company’s significant savings in terms of time and capital. The average cost required to bring a new drug to market is USD 1.24 billion by traditional drug development process, whereas in drug repurposing it costs around ≤60% expenditure of traditional drug discovery. Some other advantages are as follow. The primary focus of traditional discovery program is to discover drugs to treat chronic and complex diseases, whereas by drug repositioning approach, development of drugs for rapidly emerging and re-emerging infectious diseases, difficult to treat diseases and neglected diseases (NTDs) are focused. Due to the availability of bioinformatics or cheminformatics approaches, huge omics (proteomics, transcriptomics, metabolomics, genomics etc.) data and database resources, disease targeted-based repositioning methods can be used to explore the unknown mechanisms of action (such as unknown targets for drugs, unknown drug–drug similarities, new biomarkers for diseases etc.) of known/existing drugs .
3. Strategies of drug repurposing
There are two main strategies of DR, viz., on-target and off-target (Figure 2). In on-target DR, the known pharmacological mechanism of a drug molecule is applied to a new therapeutic indication. In this strategy, the biological target of the drug molecule is same, but the disease is different .
For example, in the repositioning of minoxidil (
4. Approaches of drug repurposing
Drug repositioning has two alternative and complementary approaches, one is experiment-based approach and the other is
The experiment-based approach is also known as activity-based repositioning which refers to the screening of original drugs for new pharmacological indications based on experimental assays. It involves protein target-based and cell/organism-based screens in
The differences between activity- and
|Experimental (||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|
Over the past few decades, the
In recent years, discovery scientists and researchers have combined
5. Methodologies of drug repurposing
The methodologies adopted in DR can be divided into three broad groups depending on the quantity and quality of the pharmacological, toxicological and biological activity information available. These are mainly (i) drug-oriented, (ii) target-oriented, and (iii) disease/therapy-oriented.
In the drug-oriented methodology, the structural characteristics of drug molecules, biological activities, adverse effects and toxicities are evaluated. This strategy is meant for identifying molecules with biological effects based on cell/animal assays. This type of repositioning methodology is based on traditional pharmacology and drug discovery principles, where studies are usually conducted to determine the biological efficacy of drug molecules without really knowing about the biological targets. Significant successes in DR have been achieved with this orientation profile, through serendipity or clinical observation, such as discoveries with sildenafil .
Target-based methodology comprise
The application of disease/therapy-oriented methodology in DR is relevant when there is more information on the disease model is available. In this case, DR can be guided by the disease and/or treatment based upon availability of information given by proteomics (disease specific target proteins), genomics (disease specific genetic data), metabolomics (disease specific metabolic pathways/profile) and phenotypic data (off-target mechanism, pharmacological targets, disease pathways, pathological conditions, adverse and side effects etc.) concerning the disease process. It, therefore, requires construction of specific disease networks, recognizing genetic expression, considering key targets, identifying disease causing protein molecules related to cell and metabolic pathways of interest in the disease model .
Figure 4 delineates the methodologies and steps involved in drug repositioning.
Drug-based phenotypic screening and target-based methods account for more than 50% of the FDA approved small drug molecules and biologics. Phenotypic drug screening methods identify drug candidates from small molecule libraries by serendipitous observations. Target-based methods discover drugs based upon known target molecules. The treatment/therapy-based repositioning methodology is similar to disease-based methodology .
A detailed enumeration of various methodologies employed in drug repositioning along with suitable examples is given in Table 2.
|Methodology||Type of method, category||Method/specific approach||Example(s)|
|Phenotypic screening||Blinded/ Target-based, Screening||Sildenafil (erectile dysfunction), rituximab (breast cancer)|
|Target 3D structure, chemical structure, information of drugs and ligands||Target-based, Cheminformatics||Fluorouracil (lung cancer), etoposide (bladder cancer)|
|Drug-target information, chemical structure, information of targets and drugs||Knowledge-based, Bioinformatics/ Chem-informatics||Drug–target prediction||Simvastatin, ketoconazole (breast cancer)|
|Clinical trial information and adverse effects||Knowledge-based, Bioinformatics||Drug similarity studies||—|
|FDA approval labels||Knowledge-based, Bioinformatics||Drug similarity studies||—|
|Available Pathway information||Knowledge-based, Bioinformatics||Discovery of disease mechanism and address of key targets||Vismodegib (skin cancer)|
|Disease omics/ genetics data||Signature-based Bioinformatics||Studying gene signatures/ genomics to identify key targets||—|
|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)|
|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)|
|Disease omics and drug omics data||Signature based, Bioinformatics||Similarities between drugs and diseases||Cimetidine (lung cancer), topiramate (inflammatory bowel disease)|
|Drug omics data, disease pathway and protein interaction network||Targeted- mechanism based, Network biology and Systems biology||Elucidating targeted pathways||Daunorubicin, clomifene (breast cancer)|
Several available repositioning methods depicted above in Table 2 are described briefly as follows:
6. Repositioned drugs
Drug repositioning is an alternative approach to traditional drug discovery. With increasing market demand many pharmaceutical companies are developing new drugs or new therapeutic uses from existing/old/available drugs by drug repositioning approaches in less time, yet at low cost. In drug discovery program, the repositioning is usually essentially carried out in two stages as described follows. In the first stage, the
Table 3 depicts examples of some repositioned drugs already developed or currently under development from various approved (FDA) or marketed drugs and investigational new drugs (IND). Some repositioned drugs currently under clinical trials in COVID-19 are also included in the list.
|Drug, pharmacological category||Original indication||New indication||Status of development|
|Amphotericin B (AMB), Anti-fungal antibiotic||Fungal infections||Leishmaniasis||Already developed *|
|Aspirin, NSAID||Pain and inflammation||CVDs (Anti-platelet)||Already developed *|
|Prostate cancer||Under development *|
|Amantadine, Anti-viral||Influenza||PD||Already developed *|
|Astemizole, Anti-histaminic||Allergic illness such as urticaria||Malaria||Under development *|
|Atomoxetine, Anti-depressant||Depression||Attention deficit, Hyperactivity disorder||Already developed *|
|Avermectin, Anthelmintic||River blindness, Elephantiasis||Tuberculosis||Under development *|
|Azithromycin, Anti-bacterial antibiotic||Bacterial infections||COVID-19||Under development *|
|Bromocriptine, Dopamine receptor antagonist||PD||DM (type 2)||Under development *|
|Bupropion, SSRI, Anti-depressant||Depression||Smoking cessation||Already developed *|
|Celecoxib, COX-2 inhibitor, NSAID||Inflammation||Breast and colon cancer||Under development *|
|Chloroquine, Anti-malarial||Malaria||COVID-19||Under development *|
|Cimetidine, H2 receptor antagonist||Gastric ulcer||Breast, lung and prostate cancer||Under development *|
|Crizotinib, ALK inhibitor||Lymphoma (under clinical trial for ALCL)||NSCLC||Already developed #|
|Colchicine, Anti-inflammatory agent||Gout (Gouty arthritis)||Pericarditis||Already developed *|
|COVID-19||Under development *|
|Daunorubicin, Antibiotic||Breast cancer||Already developed *|
|Digoxin, Cardiotonic||CVDs such as heart failure||Prostate Cancer||Under development *|
|Dimethyl fumarate, Anti-allergic||Psoriasis||Multiple sclerosis (MS)||Already developed *|
|Disulfiram, Acetaldehyde dehydrogenase inhibitor||Chronic alcoholism||Cancer||Under development *|
|Duloxetine, SSNRI||Depression||Generalized anxiety disorder, fibromyalgia, chronic musculoskeletal pain, neuropathic pain||Already developed *|
|Everolimus, Immune suppressant||Immune suppressant||Pancreatic neuroendocrine tumors||Already developed *|
|Favipiravir, Anti-viral||Influenza||COVID-19||Under development *|
|Fluorouracil, Antimetabolite, Anti-cancer||Cancer||Breast cancer||Already developed *|
|Fluoxetine, Anti-depressant||Depression||Premenstrual dysphoria||Already developed *|
|Gabapentin, Anti-epileptic||Epilepsy||Neuropathic pain||Already developed *|
|Galantamine, AChE inhibitor||Neuromuscular paralysis||AD||Already developed *|
|Hydroxychloroquine, Anti-malarial||Malaria, RA||COVID-19||Under development *|
|Ibudilast, PDE inhibitor (Anti-asthmatic)||Asthma||Neuropathic pain||Already developed *|
|Imatinib, TKI (Anti-cancer)||CML, ALL||GIST||Already developed *|
|Isoniazid, Anti-tubercular||Tuberculosis||Certain types of tumor||Already developed *|
|Itraconazole, Anti-fungal||Fungal infections||Cancer like NSCLC (Anti-angiogenic)||Under development *|
|Ivermectin, Anthelmintic (Anti-parasitic)||Scabies, river blindness, helminthiasis||COVID-19||Under development *|
|Lopinavir/Ritonavir, Anti-viral||HIV/AIDS||COVID-19||Under development *|
|Metformin, Anti-diabetic||DM (type 2)||Breast and colon Cancer, CVDs||Under development *|
|Methotrexate, Anti-metabolite (Anti-cancer)||Cancer||Psoriasis, RA||Already developed *|
|Milnacipram, Anti-depressant||Depression||Fibromyalgia||Already developed *|
|Miltefosine, Anti-leishmanial||Cancer||Leishmaniasis, Amoeba infection||Already developed *|
|Mifepristone, Antiprogestin||Termination of pregnancy in combination with misoprostol||Cushing’s syndrome||Already developed *|
|Minoxidil, Vasodilator (Anti-hypertensive)||Hypertension||Androgenic alopecia||Already developed *|
|Nelfinavir, Anti-viral||HIV/AIDS||Breast cancer, NSCLC (under clinical trials)||Under development *|
|Nitroxoline, Anti-bacterial||UTI||Breast, bladder and pancreatic cancers||Under development *|
|Orlistat, Anti-obesity agent||Obesity||Cancer||Already developed *|
|Penfluridol/Pimozide, Anti-psychotics||Psychiatric illness||Breast cancer||Under development *|
|Propranolol, β-Blocker||Hypertension||Migraine||Already developed *|
|Remdesivir, Anti-viral||Influenza, Ebola (failed in clinical trial)||COVID-19||Under development #|
|Retinoic acid||Acne||Acute leukemia||Already developed *|
|Ribavirin, Anti-viral||Viral infection such as RSV, hepatitis C infections||Cancers like leukemias and lymphomas||Under development *|
|Ropinirole, Anti-Parkinsonian drug||PD||Restless leg syndrome||Already developed *|
|Sildenafil, PDE inhibitor||Angina pectoris, Pulmonary arterial hypertension||Erectile dysfunction||Already developed *|
|Simvastatin, Hypolipidemic||CVDs||Lung cancer||Already developed *|
|Sunitinib, TKI (Anti-cancer)||Imatinib-resistant GIST, RCC||Pancreatic neuroendocrine tumors||Already developed *|
|Tamoxifen, Anti-estrogen (Anti-cancer)||Breast cancer, Anticancer||Systemic lupus erythematosus||Already developed *|
|NTDs like Leishmaniasis (in combination with miltefosine)||Under development *|
|Thalidomide, Immune modulator||Immunomodulation, Morning sickness (withdrawn)||Multiple myeloma, Leprosy||Already developed #|
|Tocilizumab, IL-6 inhibitor (Immune modulator)||RA||COVID-19||Under development *|
|Topiramate||Fungal infections||IBD||Already developed *|
|Valproic acid, Anti-epileptic||Epilepsy||Manic depression (bipolar disorder), migraine headache||Already developed *|
|Valsartan, ARB (Anti-hypertensive)||Hypertension, Heart attack||AD||Already developed *|
|Zidovudine, Anti-viral||Cancer (failed clinical trial)||HIV/AIDS||Already developed #|
Colchicine, a well-known anti-inflammatory drug used in the treatment of gout and pericarditis, is currently under clinical trial for treating COVID-19 patients. This drug has been proved to be effective in preventing massive cytokine storm induced pneumonia caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). The antiviral effect of an older antimalarial drug, chloroquine (used as phosphate salt) against SARS-CoV-2 infection has also been investigated worldwide. Studies suggest that chloroquine may be beneficial in preventing coronavirus induced pneumonia in COVID-19. As per recent reports from NIH (National Institutes of Health, US), the clinical trial of a combination of hydroxychloroquine/azithromycin for the treatment of COVID-19 patients has already been started. In this combination, both the drugs are FDA approved, where hydroxychloroquine is an antimalarial drug and azithromycin is an antibacterial antibiotic. An anti-viral drug, favipiravir intended for the treatment of influenza is currently under phase-2/phase-3 clinical trials on COVID-19 patients around the world (China, Japan, US, India). Glenmark has initiated phase-3 trial on favipiravir for the treatment of COVID-19 patients in India. An investigational anti-retroviral drug called remdesivir (originally developed by Gilead Sciences Inc. for the treatment of Ebola, but failed in clinical trial) is also under clinical trial for treating COVOD-19 patients in several countries like China, US, UK and India. In India, clinical trials on favipiravir, remdesivir and colchicine are currently underway by CSIR (Council of Scientific & Industrial Research) laboratories. A fixed dose drug combination called lopinavir/ritonavir earlier approved to treat HIV/AIDS under the brand name
7. Opportunities and challenges
On contrary to traditional drug discovery program (a complex and time consuming process with high cost of development and risk of failure), drug repositioning, reduces the time and cost of drug development. Drug repositioning is also a low-risk strategy. Computational or machine learning approach has significantly improved the performance of drug repositioning. In comparison to computational approaches, using experimental approaches (such as target protein-based screening, cell-based assay, testing in animal model, and clinical testing) that provide direct evidence-based understanding of links between drugs and diseases are more reliable and credible. However, in recent years computational approaches are usually combined with the experimental approaches to identify new indications for old drugs, called mixed approaches. In this approach, computational methods are validated by biological experiments and clinical tests. Mixed approach of repositioning offers a rational and exhaustive exploration of all possible repositioning opportunities, taking into consideration improved access to available databases and technological advances. Furthermore, the R&D investment required for drug repositioning is lower than that for traditional drug discovery. Thus, drug repositioning offers an opportunity for many pharmaceutical companies to develop drugs with lower investments [27, 28]. Mixed approach of DR offers opportunities for developing repositioned drugs more effectively and rapidly. From the market perspective, a large number of diseases require new drugs to be treated with a potential market demand and economic impacts. For example, the discovery of drugs for rare/neglected diseases has a large potential market to explore. There is, therefore, an opportunity for repurposing of drugs for the treatment of rare, neglected, orphan diseases or difficult to treat diseases. There are over 6000 rare diseases that lack proper treatment. About 5% of them are being researched. Rare diseases have a large potential market to explore. Given the high attrition rates, substantial costs and slow pace of drug discovery and development, repurposing of old drugs to treat both common and rare diseases is increasingly becoming an attractive area of research because it involves the use of drug molecules with reduced risk of failure at shorter time and lower cost development [30, 31, 32, 33].
With the advent of technologies such as genomics, proteomics, transcriptomics, metabolomics, etc., and availability of huge databases resources including drug omics data, disease omics data, etc., there are a plenty of opportunities to discover drugs by drug repositioning in a collective and integrated effort of all the above methods/approaches mentioned above. Researchers are currently equipped with the latest reliable tools and data to explore the novel unknown mechanism of actions/pathways based upon disease-specific target proteins/genes and/or specific biomarkers associated with the progression of the disease [34, 35].
Various databases and software are available publicly for genomics, proteomics, metabolomics and pathway analysis. Several computational strategies are already developed to increase the speed and ease of the repurposing process. Some important databases used in drug repositioning studies are outlined in Table 4.
However, opportunities come often with many challenges in drug repositioning. The identification of a new therapeutic indication for an existing drug poses a major challenge in repositioning. However, drug repositioning is a complex process involving multiple factors such as technology, commercial models, patents, and investment and market demands. Some multiple challenges which include choosing the right therapeutic area for the drug under investigation, issues related to clinical trials such as need to run new trials from start if the data from clinical or preclinical trials for the original drug or drug product are outdated or are not satisfactory [34, 35].
8. Regulatory and intellectual property issues
Traditional drug development strategies are costly, failure prone and expensive ventures. Therefore, drug repositioning has recently drawn considerable attention to discover drugs with new therapeutic uses with the goal to bring drugs out at comparatively faster rate for clinical use. Some regulatory issues that are commonly encountered in drug repositioning are described as follows [37, 38]. As per regulatory guidelines, new preclinical and/or clinical trials may be required to be carried out if the available data are not satisfactory and do not comply with the requirements of regulatory agencies such as FDA or EMA. Another important issue is related to patent application and intellectual property rights (IPR). There are no provisions of IP protection of drug discovery by repositioning approach as per the IP and patent laws. For repositioned drugs, IP protection is limited. For repositioning drugs, IP protection is limited. For example, some novel drug-target disease associations found by repositioning researchers were confirmed by publications or online databases; however, it is difficult to seek IP protection for such associations because of the law. The IP issue prevents some repositioned drugs from entering even into the market [39, 40]. Moreover, some repositioning projects are forced to be abandoned, which is a waste of time, money and lot of efforts. Although many omics data and medical databases have been established, selecting the appropriate approach for repositioning is still a challenge due to the regulatory issues because massive amounts of data may not be valid if not obtained from reliable sources. It is, therefore, necessary that researchers or manufacturers must strictly adhere with standard regulatory guidelines for drug discovery by repositioning approaches [2, 41, 42, 43].
Traditionally, the dug repurposing has a long recorded history discovery of drug molecules particularly through serendipitous observations. In recent years, it has embarked a new avenue in the development of new therapies based upon existing/approved medicines. The strategic drug repositioning in a more systematic and rational way has brought innovation with the discovery of drug molecules with unknown therapeutic indications. As drug repositioning approach offers significant reduction in R&D costs, greater chances of success, shorter research time and lower investment risk, it has gained increasing market demands. Because these advantages are beneficial for discovery scientists, drug researchers, consumers and pharmaceutical companies, enabling the application of novel approaches of repositioning strategy in the drug discovery program for almost all human diseases. Moreover, the use of
Conflict of interest
Authors declare that there is no conflict of interest.