**4. Concluding remarks and perspectives**

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

repurposing process.

stromal tumors [79].

in human diseases [84].

targets or biomarkers.

**3.2 Computational approaches**

**3.1 Experimental approaches**

of appropriate drugs for potential indications is crucial for production of candidate compounds. At present, two approaches are widely used for drug repurposing including experimental screening approaches and molecular docking by computer. In the following items, we make a detailed description of these two methods in drug

Experimental screening approaches are usually regarded as the first stage in the process of drug discovery and drug repurposing. Proteomic techniques such as affinity chromatography and mass spectrometry have been widely employed to identify drug candidates [75]. Nowadays, drug target analysis and drug repurposing are inseparable. Drug repurposing is distinct from drug discovery in terms of alteration of drug target. Cellular thermo stability assay technique can predict the affinity of drug ligands by mapping the contact patterns of intracellular targets [76]. The molecular on and off targets have been disclosed for many clinically approved drugs via this method. Especially in the field of kinases, new targets of well-known drugs are obtained through affinity matrices [77, 78]. For example, imatinib, a tyrosine kinase inhibitor, has been successfully reused in the treatment of gastrointestinal

In addition, chemical compounds with disease-related effects can be defined in the model through phenotype screening [80]. Phenotype screening has always been more successful than target screening in the facet of drug development [81, 82]. In the case of drug repurposing, if the compounds selected through phenotypical assays are approved clinical drugs or ongoing clinical trials, they are probable to reuse. Several drugs approved for tobacco dependence have been evaluated, and it has been found that topiramate changes nicotine- or ethanolinduced behavior in zebrafish models [83]. However, there are some challenges that the efficacy of drug candidates in in vitro experiments require to be validated

Molecular docking by a computer is also an important method for evaluating drug target binding kinetics and drug residence times of existing drugs or drug candidates [85]. Large amounts of computational drug repositioning methods choose transcriptomic data to identify potential new indications for drugs. Furthermore, these methods have applied techniques such as comparison of gene expression profiles between a disease model and drug-treated condition [86], network integration [87], prediction of drug-protein interactions [88], and utilization of genotype–phenotype associations. Recently, a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation

Score/Class (DRPS/C) for Alzheimer's disease occurs on the basis of inverse associations between disease-induced or drug-induced gene and protein perturbation patterns [89]. Briefly, these approaches can be applicable to discovery of drug

It should be considered that for many neurological disorders, drugs require good penetration into BBB. Then, the therapeutic approaches of targeting brain have been classified as invasive and noninvasive categories [90, 91]. The invasive approaches contain the temporary increase of BBB permeability, and noninvasive approaches involve modification of drug molecule via physiological, chemical, or colloidal carrier system approach. Meanwhile, these methods are also related

**86**

Drug repurposing is a vital strategy for developing new therapeutic values of existing drugs or drug candidates due to its ability to save time and reduce cost [96]. This type of innovative concept will undoubtedly expedite the drug development process. Meanwhile, some limitations need to be considered during drug repurposing process in neurological diseases. Owing to complex molecular and cellular signaling mechanisms in neuropathological states, drug repurposing may be difficult. Additionally, drugs not only respond to a single target but also affect multiple targets [97], causing a variety of adverse reactions. A comprehensive assessment of the advantages and disadvantages of these side effects can help us understand drug repositioning from a more all-round perspective [98, 99].

In order to overcome limitations faced during drug repurposing, we make proposals in the following descriptions. Firstly, it is foremost to establish a comprehensive data analysis platform to maximize data sharing. Information science services and artificial intelligence can help unlock and reanalyze the large amount of data accumulated by approved drugs or drug candidates to clinical trials. These data may be stored in a diversified way. Storage locations, formats, and types may vary, including different storage locations, formats, and types. The data obtained from clinical trials and biological databases are too large and complex that the traditional data processing methods cannot deal with it, which leads to the bottleneck in the research process [99]. Big data can significantly improve our understanding of the disease and make more accurate disease-related strategies. However, there is a big gap between generating biomedical data and data analysis [99, 100]. To ensure the efficiency of research, it takes time, energy, and expertise to find technical solutions to integrate them. Secondly, it is encouraged to provide more financial support for clinical trials of drug repurposing, including technical support. The preclinical research of drug repurposing requires financial support to obtain the data in clinical trials. In this case, drugs that can be developed to treat rare diseases are more likely to apply in clinical neurological diseases therapeutics [101]. Finally, in order to facilitate drug repurposing process, we advocate it is indispensable to solve patent restrictions and take reasonable supervision. All applications of drug repurposing should be accompanied by a risk management plan. Drug's safety can be supported by clinical trial data or post marketing data.

In conclusion, drug repurposing is a novel approach for expediting drug development process in neurological diseases. Repurposed drugs may provide an efficient avenue for improving a plethora of pathological conditions including neurological disorders. In the future, it is essential to exploit molecular mechanisms during drug repurposing processes due to the possibility that targets of repurposed drugs in neurological diseases are distinct from original targets in treating other diseases, in order to make these drugs more effective and safe.
