Studies of natural product repositioning in FAB-Lab.
Abstract
The withdrawal of several blockbuster drugs due to severe adverse effects and the failure of several developed drugs in clinical trials raised questions about the efficacy of current approaches of drug discovery. Moreover, the limitation of resources and the long and costive process of drug discovery made a lot of pharmaceutical companies to employ drug repurposing strategies to get new insights about activities that were not considered during their initial discovery. The development of therapeutics for treatment of dermatological condition is not considered as priority although it affects the lifestyle of thousands of people around the world. Serendipity and observations have contributed significantly in this field but immerse efforts have been exerted to find systematic methods to identify new indications for drugs, especially with the unprecedented progress in molecular biology and omics. So, in this chapter, we will emphasize on different approaches used for drug repositioning and how it was applied to find new therapeutics for different dermatoses.
Keywords
- drug repositioning
- alopecia
- psoriasis
- acne
- hirsutism
- hyperpigmentation
1. Introduction
In the early years of this century, it was expected that revolutionary development in industry and technology will allow an unprecedented opportunities for drug discovery and development; however, the disappointing rate of drug approval in the last 20 years shed the light on the urgent need to reassess the efficiency of current strategies of drug discovery.
Despite the large amount of investment that has been put in drug development, several drug candidates fail to pass due to pharmacokinetic issues or severe side effects that mainly are not demonstrated until clinical phases, which lead to extreme economic loss to pharmaceutical companies that might spend more than billion dollars in the process.
These facts were not overlooked by pharmaceutical industries or academia; so, they started to apply a new strategy that embraces new application of approved drugs rather than starting from scratch, which is known as drug repositioning. While the term was first coined in 2004, the approach has already led to the discovery of several therapeutic agents in the last century; however, serendipity, trials, and errors were the main players in most of these cases.
This means that harnessing our highly advanced tools of molecular biology and computational techniques would guarantee the rediscovery of new indications for already approved drugs, which will not only increase our arsenal of therapeutic agents but also will drastically decrease the time and costs of the whole process.
Moreover, this approach could help for finding therapeutic solutions for orphan diseases or clinical conditions that affects low number of population which are usually neglected by pharmaceutical corps as in the case of dermatologic therapeutics due to the low prevalence of many dermatoses and the inappropriate estimation of the burden of psychological and physical impact of skin disorders on the quality of life.
Indeed, the field of dermatology covers wide range of disorders, but this means that drug repurposing strategy may be uniquely successful, hence the broad variety of pathophysiological process affecting the skin. In that aspect, the liver research laboratory (FAB-Lab, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt) has utilized several approaches for not only optimization and enhancing the therapeutic effect of commonly available natural products but also recognizing novel application for them so that one therapeutic agent could be used for treatment of several or complex conditions (Table 1). In this chapter, we will review different strategies for drug repositioning and their application in dermatological and cosmeceutical field.
No. | Studies for discovery of new indications for natural products | Ref | |
Compounds | Indication | ||
1. | Compounds from frankincense | Anti-herpes | [1] |
2. | Frankincense oil | Immunomodulatory activity | [2] |
3. | Myrrh standardized extract | Schistosomicidal | [3] |
4. | Free-B-ring flavonoids | Colon cancer | [4] |
5. | Anti-neoplaston A-10 | Immune-modulatory in breast cancer patients | [5] |
6. | Ricinine alkaloids analogs | Oral squamous cell carcinoma | [6] |
7. | Stemmadenine alkaloid derivative | Antiproliferative activity against different cancers | [7] |
8. | Curcumin | Iron accumulation in liver | [8] |
9. | Cucurbitacin B | Chemo-sensitization of cisplatin-resistant ovarian cancer | [9] |
10. | Bi-aryl methyl eugenol analogs | Breast cancer invasion inhibitors | [10] |
Studies for discovery of new target for natural products | |||
Compounds/extract | Targets | ` | |
1. | Flavonoids containing an alpha-keto group | Tyrosinase inhibitors | [11] |
2. | Cycloartane glycoside | Lactate dehydrogenase inhibitor | [12] |
3. | Betulinic acid analogs | Topoisomerase inhibitors | [13] |
4. | Gingerol derivatives | LTA4H inhibitory activity | [14] |
5. | Curcumin derivative | Alpha-amylase inhibitory | [15] |
6. | Glycyrrhizin derivative | Acetylcholinesterase inhibitory activity | [16] |
2. Drug repositioning strategies
Drug repositioning is achieved by understanding of molecular mechanisms of drug action and by identification of the interacting proteins of the drug. In many cases, molecular mechanism of drug action is poorly understood or completely unknown. The drug action can be observed by identification of drug targets and their specific interactions, drug-induced change in expression of a specific gene and the associated pathways, and change in disease phenotypes.
Current approaches for drug repositioning come from the so-called “drug action spectrum” concept as shown in Figure 1, which is based on three paradigms, namely, target-centric, drug-centric, and disease-centric repositioning. The first and second modules are closely related and usually applied interchangeably; the target-centric module focuses on finding new indication for the already established target; for example, the discovery of the role of androgenic receptor in hair loss allowed the repurposing of finasteride for treatment of androgenic alopecia.
Drug-centric module aims in finding a new target for therapeutic agent, experimental or abandoned drugs; for example, the notorious thalidomide, which was firstly indicated for treatment of nausea and caused the phocomelia crisis, has been repurposed for treatment of myeloma and several dermatological conditions related to immune diseases.
These types of repositioning use computational ligand- and structure-based techniques [12, 13], chemical proteomics [16, 17], and off-target screening to identify potential therapeutic applications; so, we will explain the theory behind its approach and its application in drug repositioning.
In the third module, the repurposing depends on the similarity of pathophysiological nature of diseases; for example, different types of cancers or different autoimmune diseases which allow the expansion of drug to a closely related indication so that extensive analysis of the associated molecular targets may not be required. Nevertheless, this type of repositioning strategy is the most observed type in drug repurposing field; it is worthy to note that retrospective analysis of several repurposing cases could be explained exclusively by drug-target interaction [18].
The main tools used for applying disease-centric repositioning are gene or protein expression profiling [14, 15], phenotypic screening [11], clinical observations [19], side effect analysis [20], and data mining and neural networks [21, 22]. In the following section, we will shed the light on the application of these tools in drug repositioning, especially in dermatology.
2.1 Application of drug-target interaction in drug repositioning
2.1.1 Ligand- and structure-based approaches
Ligand-based approaches are usually employed when no structural information about the target under investigation is available. They are not only used for virtual screening but also for lead optimization [17]. The key concept in ligand-based approaches is to determine common structural features or descriptors that could be found in compounds with the same pharmacological activity; therefore, pharmacophoric function groups which are necessary to maintain the activity could be elucidated (Figure 2) [19].
In structure-based approach, the 3D structure of biological target is used to recognize how an active compound bind to its active site; hence, molecular docking could be used for identifying other drugs that can bind to the active site in similar fashion [20]. It is worthy to note that such approach could be used also for identifying the ability of drugs to bind to diverse types of targets, which is known as target fishing or inverse docking; this could be achieved by docking drug of interest against database of targets of clinical significance (Figure 3) [21].
Indeed, drug repositioning cases derived from this approach are still limited, but it has been extensively used to give insights on the mode of action of natural products and the rationale behind their use in traditional medicine. For example, ricinoleic acid
Bagherzadeh et al. applied pharmacophore and structure-based virtual screening to identify tyrosinase inhibitor from zinc database; among them, five compounds showed the potential to be used as potent inhibitor according to molecular dynamic simulation [26]. Interestingly, Choi et al. used structure-based virtual screening for repurposing thiopurine drugs such as mercaptopurine
2.1.2 Off-target-based repositioning
The ability of most of drugs to induce side effects is originated from their binding with other targets that might share certain homology with the original targets, so it could be quite handful to use this drugs in treatment of diseases where these targets are dysregulated.
Spironolactone
Another intriguing example for off-targets drug repositioning is doxepin
Off-target effects are also influenced by the route of administration; sodium valproate
However, sodium valproate topical treatment induced hair growth in male C3H mice model, which could be explained by its ability to inhibit glycogen synthase kinase 3β and activation of Wnt/β-catenin pathway, which in turn, is associated with hair regeneration and anagen induction. This result was supported by randomized interventional study, where 7.2% spray of sodium valproate applied twice daily on scalp up to 24 weeks showed the efficacy of valproate spray on androgenic alopecia.
Dapsone
Finally, thalidomide
2.1.3 New target indication-based repositioning
In this approach, data analysis based on omics is used to identify new function instead of finding new targets for certain chemical entity; hence, it might be the most challenging approach as it depends on the advances of molecular biology tools which can reveal the role of already known target in completely different diseases.
Finasteride
Another example is the repositioning of eflornithine
Zileuton
2.2 Disease-centered drug repositioning
2.2.1 Application of data mining and omics in drug repositioning
In disease-centered paradigm, the observation and analysis of data from phenotypic assays, clinical trials, and literature could be an important resource for drug repositioning, as previously mentioned, this type of repositioning is oriented toward the clinical outcomes rather than the exact molecular mechanism behind the drug switch; from other angle, the researcher aims to find certain fingerprint on the genetic or proteomic level to support the repositioning hypothesis; for example, the transcriptomic analysis of different types of autoimmune diseases could reveal similar pattern of gene expression, which means that the same drug could be used for different types of immunity-related condition.
Qu et al. applied integrative clinical transcriptomic analyses for finding new drugs for treatment of psoriasis. First, gene expression analysis of samples collected from psoriasis patient and normal volunteers were used to identify molecular targets associated with the disease, and then, connectivity map analysis revealed potential drugs for the identified targets, which were resveratrol
Also, Patrick et al. gathered drug-related information from more than 20 million articles using machine learning based on word embedding to build a model that highlights drug-disease relationship in order to repurpose drugs for treatment of immune-mediated dermatological conditions, where prednisone
2.2.2 Clinical observation-based drug repurposing
Bimatoprost
Phenytoin
Bevacizumab, a monoclonal antibody that is used for treatment of several types of cancer, was observed to achieve complete remission of psoriasis in metastatic colon cancer without any other treatment for psoriasis [37]; a case which was reported again in another study that described the same effect in metastatic renal cell cancer, psoriasis, and psoriatic arthritis patient, which means the bevacizumab could be repurposed for treatment of these dermatoses; also, it sheds the light on the importance of (VEGF) as a target for treatment of inflammatory skin conditions [38].
The Janus kinase (JAK) inhibitor, tofacitinib
Metformin
Finally, minoxidil
2.2.3 Phenotypic screening for drug repositioning
Niclosamide (NCL)
Hall et al. used zebrafish neutrophil migration assay, for evaluation of the suppressive effect of 1280 approved drugs on recruitment of neutrophils; where drugs showing prominent anti-inflammatory activity were further tested in atopic dermatitis animal model, among them 11 drugs which was not reported previously as anti-inflammatory agent [48].
Chang et al. used in vivo model of chemically induced murine skin tumorigenesis to confirm the hypothesis of repositioning of beta blocker for treatment of skin cancer, since several studies showed that stress-related catecholamine hormone expression can affect tumor progression [49].
Carvedilol
Cannabidiol (CBD)
3. Concluding remarks and future perspective
Drug repositioning is an important strategy to maximize the benefits from already approved drugs; it will not only contribute to reduction of time and cost for drug discovery but also could help to develop new therapeutics for orphan and ignored diseases. While historic cases of drug repositioning were inspired by serendipity and observations, more systematic approaches became well established by time. In silico and data mining tools could help to analyze the large amount of data available from omics, phenotypic assay, and clinical investigations by revealing novel relationship between drugs, targets, and different pathways of diseases as described in this chapter; the integration of different tools of drug repurposing will allow the identification of safe and effective therapeutics for treatment of dermatological condition and enhance the quality of life of patients.
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