**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 [12].

For example, in the repositioning of minoxidil (*Rogaine*), an on-target profile is observed, since the drug acts on the same target and produces two different therapeutic effects. Minoxidil was transformed from an antihypertensive vasodilator anti hair loss drug. As an antihypertensive vasodilator, minoxidil has the property of widening blood vessels and opening potassium channels, which allows more oxygen, blood, and nutrients to the hair follicles and this pharmacological action helps its use in the treatment of male pattern baldness (androgenic alopecia).

**7**

**Table 1.**

assay

information

screening

*Drug Repurposing (DR): An Emerging Approach in Drug Discovery*

On the other hand, in the off-target profile, the pharmacological mechanism is unknown. Drugs and drugs candidates act on new targets, out of the original scope, for new therapeutic indications. Therefore, both the targets and the indications are new [1]. Aspirin (*Colsprin*) is good example of the off-target profile. Aspirin has been traditionally used as NSAID in the treatment of various pain and inflammatory disorders. It also suppresses blood coagulation (clot formation) by inhibiting the normal functioning of platelets (antiplatelet drug). It is, therefore, used in the treatment of heart attacks and strokes. Another new use of aspirin in the treatment

Drug repositioning has two alternative and complementary approaches, one 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 *in vitro* and/or *in vivo* disease models without requiring any structural information of target proteins. Several approaches of experimental repositioning are target screening approach, cell assay approach, animal model

In contrast, *in silico* repositioning carries out virtual screening of public databases of huge drug/chemical libraries using computational biology and bioinformatics/cheminformatics tools. In this approach, the identification of potential bioactive molecules is achieved based upon the molecular interaction between drug

The differences between activity- and *in silico*-based approaches of drug reposi-

Over the past few decades, the *in silico* approach has gained wide popularity with significant success in drug discovery program. Many pharmaceutical companies and drug discovery research laboratories have already successfully incorporated the *in silico* tools and techniques for the drug discovery from structurally diverse chemical spaces since a large amount of information on the chemical structure bioactive compounds, structure of proteins and pharmacophore models are available in the public domain. Moreover, *in silico* repositioning has some advantages over the experimental-based approach, which includes reduced time and cost of development and low risk of failure. The limitation of this method is that it requires

Protein target-based screening

information

Requires structural information of target proteins and drug-induced cell/disease phenotypic

Higher rate of false positive hits during the screening

experiment-based approach and the other is *in silico*-based approach.

**Activity-based approach** *In silico***-based approach**

Time and labor consuming Time and labor efficient

*Differences between activity- and* in silico- *based approaches of drug repositioning [17, 18].*

Experimental (*in vitro* and *in vivo*) screening Computational (virtual) screening

*DOI: http://dx.doi.org/10.5772/intechopen.93193*

of prostate cancer has also been reported.

**4. Approaches of drug repurposing**

approach and clinical approach [15, 16].

molecule and protein target [17].

tioning are summarized in **Table 1**.

Target-based and cell/organism-based screening

Requires no structural information of target proteins and drug-induced cell/disease phenotypic

Lower rate of false positive hits during the

**Figure 2.** *On-target and off-target strategies of drug repositioning.*

*Drug Repurposing (DR): An Emerging Approach in Drug Discovery DOI: http://dx.doi.org/10.5772/intechopen.93193*

On the other hand, in the off-target profile, the pharmacological mechanism is unknown. Drugs and drugs candidates act on new targets, out of the original scope, for new therapeutic indications. Therefore, both the targets and the indications are new [1]. Aspirin (*Colsprin*) is good example of the off-target profile. Aspirin has been traditionally used as NSAID in the treatment of various pain and inflammatory disorders. It also suppresses blood coagulation (clot formation) by inhibiting the normal functioning of platelets (antiplatelet drug). It is, therefore, used in the treatment of heart attacks and strokes. Another new use of aspirin in the treatment of prostate cancer has also been reported.

### **4. Approaches of drug repurposing**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

known/existing drugs [13].

**3. Strategies of drug repurposing**

molecule is same, but the disease is different [12].

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

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

For example, in the repositioning of minoxidil (*Rogaine*), an on-target profile is observed, since the drug acts on the same target and produces two different therapeutic effects. Minoxidil was transformed from an antihypertensive vasodilator anti hair loss drug. As an antihypertensive vasodilator, minoxidil has the property of widening blood vessels and opening potassium channels, which allows more oxygen, blood, and nutrients to the hair follicles and this pharmacological action helps its use in the treatment of male pattern baldness (androgenic alopecia).

**6**

**Figure 2.**

*On-target and off-target strategies of drug repositioning.*

Drug repositioning has two alternative and complementary approaches, one is experiment-based approach and the other is *in silico*-based approach.

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 *in vitro* and/or *in vivo* disease models without requiring any structural information of target proteins. Several approaches of experimental repositioning are target screening approach, cell assay approach, animal model approach and clinical approach [15, 16].

In contrast, *in silico* repositioning carries out virtual screening of public databases of huge drug/chemical libraries using computational biology and bioinformatics/cheminformatics tools. In this approach, the identification of potential bioactive molecules is achieved based upon the molecular interaction between drug molecule and protein target [17].

The differences between activity- and *in silico*-based approaches of drug repositioning are summarized in **Table 1**.

Over the past few decades, the *in silico* approach has gained wide popularity with significant success in drug discovery program. Many pharmaceutical companies and drug discovery research laboratories have already successfully incorporated the *in silico* tools and techniques for the drug discovery from structurally diverse chemical spaces since a large amount of information on the chemical structure bioactive compounds, structure of proteins and pharmacophore models are available in the public domain. Moreover, *in silico* repositioning has some advantages over the experimental-based approach, which includes reduced time and cost of development and low risk of failure. The limitation of this method is that it requires


#### **Table 1.**

*Differences between activity- and* in silico- *based approaches of drug repositioning [17, 18].*

**Figure 3.** *Approaches of drug repositioning.*

precise structural information about drug targets and in case, the protein target is not available, disease specific phenotypic or genotypic profiles of drugs are required [19]. **Figure 3** represents the approaches of drug repositioning.

In recent years, discovery scientists and researchers have combined *in silico* and experimental approaches to identify new therapeutic indications for existing drugs, called mixed approach. In the mixed approach, the result of computational methods is validated by pre-clinical biological experiments (*in vitro* and *in vivo* tests) and clinical studies. The simultaneous application of computational and experimental methodologies in a systematic manner offer a robust and logical approach to the discovery of new indications, demonstrating a greater efficiency than the discovery based on serendipity. Further, mixed approach offers opportunities for developing repositioned drugs more effectively and rapidly. This approach is credible and yet, reliable [20].
