V. DISCUSSION
4.5 Position of Current Study
The traditional method of drug discovery is a time-consuming and expensive process. The advancement computing technology brought changes in drug discovery. These include incorporation of in silico approach to that in vitro and in vivo strategies in the traditional drug discovery. In silico approach is far efficient in term of cost and time (Singh, 2021). However, since in silico does not give experimental result, therefore, its result must need a validation through in vitro and in vivo to prove its predictivity (Benfenati et al., 2010; Sacan et al., 2012).
There are numerous tools, namely target identification, drug/ligand screening, and ADME-Tox assessment in the in silico and they depend on the objective of the study. This study, for example, aimed to screen the phenolic compounds in banana peel to find a potential inhibitor for PTP1B.
Because the target of the drug has been known (i.e., PTP1B), target screening was omitted. Then, the in silico approach started with ligand-based (QSAR), structure-based (molecular docking and molecular dynamics) screening, and lastly the ADME-Tox prediction. Through various tools of in silico approach, time and cost needed to develop a new drug are substantially reduced.
After the lead compound(s), that is the most potential ligand, in this case is urolithin A and chrysin, have been identified they can be extracted or synthesized and validated in vitro and in vivo. In antidiabetic study, various types of in vitro assays can be used to validate the in silico prediction, including but not limited to cell-based assay (e.g., cellular glucose uptake) and
enzyme assay (e.g., enzyme inhibition and kinetics) (Doan et al., 2018). Additionally, in vitro assay is used to verify the inhibition or promoting effect of the ligands as in silico is not able to do that albeit robust in screening, calculating binding energy, and analyzing the binding interaction. Meanwhile, in vivo assay can be used to assess the antidiabetic activity in the living organism, mainly by observing the attenuation of blood glucose level of drug-induced diabetic animal (Naz et al., 2019). Additionally, toxicology and pharmacokinetics study can be done in vivo. However, due to ethical concern, in vitro toxicity assay is preferrable at the initial validation, yet cannot fully displace in vivo (Fischer et al., 2020).
4.6. Limitation of the Study
There are several limitations to take into account. Firstly, as explained in previous section, this study is in silico study, thus it did not provide experimental data to confirm and prove the antidiabetic and PTP1B inhibition activity; still, it could suggest the most potential drug candidate. Therefore, further validation is needed to prove the current findings. Secondly, due to cost and time constraint, the ligands screened in this study were based on the previous studies by other researchers. This would result in the differences in the species of banana, yet it was circumvented by tracing back the species where the specific compound was found. Ideally, phenolic compound extraction and identification should take place before the in silico approach.
VI. CONCLUSION
Phenolic compounds from banana (Musa spp.) have been successfully screened for their potential as PTP1B inhibitor, a novel antidiabetic target for the treatment of DM. As an initial screening, QSAR analysis using PASS SERVER was able to converge the optimal ligands to specifically inhibit PTP1B down to 18 ligands. Molecular docking has shown 8 ligands that have lower binding energy compared to the control, with urolithin A and chrysin having the lowest value. Both of them were acceptable according to Ro5 and had a good HIA and no BBB penetration, but their mutagenicity, carcinogenicity, skin and eye sensitivity were still questionable. According to molecular dynamic simulation, both urolithin A and chrysin showed a stable conformation with PTP1B. Thus, the current work indicates the potential PTP1B inhibitor from banana peel, most notable urolithin A and chrysin. Further investigation through ligand structure improvement derived from the ligands in this study for a better inhibitory effect towards PTP1B. Moreover, experimental in vitro and in vivo study are also necessary to prove the predictions in this study.
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