protein via AutoDock Vina. From the 2471 drugs, 128 FDA-approved drugs were

found to be suitable, with 18 drugs reported with antiviral effects. Virtual screening

was performed on the 18 drugs with ACE-2, 3CLpro, PLpro, HR1, and TMPRSS2

via PyRx 0.8 software. Of the 18 drugs, 7 drugs were most favourable and deemed as

promising DR candidates, namely, glecaprevir, simeprevir, ledipasvir, paritaprevir,

glycyrrhizic acid, Hesperidin, and TMC-310911.

Using the LigPlot program, glycyrrhizic acid and hesperidin showed the highest

number of H-bond interaction with ACE2 and RBD amongst all candidates.

Glycyrrhizic acid, an active ingredient obtained from the roots of the licorice

plant, has been proven to show positive effects in numerous viral diseases, such as

herpes simplex type 1 (HSV-1), varicella zoster virus (VZV), HIV, SARS, and

Epstein-Barr virus (EBV). On the other hand, hesperidin is a flavonoid extracted

from citrus fruit, which has been demonstrated to inhibit replication in influenza A

virus (IAV). Apart from that, hesperidin exhibits potent 3CLpro inhibition, an

effective target for SARS-CoV-2. Conclusively, the importance in computational

approach for DR is once again affirmed, especially in an urgent pandemic such as the

current ongoing COVID-19.

5.4

Challenges of DR

5.4.1

Optimization of Repositioned Drugs, Intellectual Property,

and Compound Availability

Although DR offers great benefits and opportunities over the de novo drug discov-

ery, there are also some drawbacks, gaps, and challenges that come along the way.

According to Pritchard et al. (2017), if the repositioned drug is intended for a new

population, or if the dosage and delivery method of the drug needs to be optimized,

clinical trials including animal models, followed by a clinical program, are still

required to test its safety. Normally, phase III of a clinical trial is a very lengthy

process, presenting itself as one of the obstacles in the development of repositioned

drugs. In unprecedented cases, the duration may be reduced when the number of

incidences is relatively low during the AD recruitment process of a clinical trial. For

example, the clinical trial conducted for COVID-19 in China using the repositioned

drug, remdesivir, was halted due to an inadequate number of infected patients to

achieve the requirement of a trial recruitment target (Wang and Xu 2020).

Concerns regarding intellectual property (IP) also arise as repositioned drugs

need to endure a strenuous process to be patented, because it has been publicly

unveiled. However, the eligibility for obtaining IP protection varies between

jurisdictions across the globe (Lexology 2021). Consequently, it may discourage

pharmaceutical companies from the opportunity to generate more revenue and

retrieve as much profitable development costs of the repositioned drug to resemble

that of a de novo drug discovery (Rastegar-Mojarad et al. 2015; Nosengo 2016).

Companies may experience financial distress, eventually resulting in interference of

the drug development process. Therefore, it is crucial to seek clarity on up-to-date

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