Published at : 27 Nov 2020
Volume : IJtech Vol 11, No 5 (2020)
DOI : https://doi.org/10.14716/ijtech.v11i5.4332
|Muhamad Sahlan||Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI Depok, West Java 16424, Indonesia|
|Muhammad Nizar Hamzah Al Faris||Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI Depok, West Java 16424, Indonesia|
|Reza Aditama||Biochemistry Research Group, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Bandung, West Java 40132, Indonesia|
|Kenny Lischer||Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI Depok, West Java 16424, Indonesia|
|Apriliana Cahya Khayrani||Department of Chemical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI Depok, West Java 16424, Indonesia|
|Diah Kartika Pratami||Lab of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Pancasila University, Jakarta, 12640, Indonesia|
Diabetes mellitus is one of the metabolic diseases, characterized by hyperglycemia, which is usually caused by endogenous glucose production through gluconeogenesis. Furthermore, fructose 1,6-bisphosphatase (FBPase), which is the last enzyme involved in gluconeogenesis, is used as inhibition target due to its relatively safe effect. In addition, It is known that propolis has shown antidiabetic activity through some sets of mechanisms due to its varied constituents. Therefore, this study aims to explore the antidiabetic activity of South Sulawesi propolis compounds against the allosteric site of FBPase (PDB ID: 3KC1) through molecular docking on Autodock Vina. The results show that 18 out of 30 propolis compounds outweigh AMP affinity. Furthermore, only two flavonoids showed 100% interaction similarity to the re-docked native ligand and AMP natural inhibition. These two compounds were Broussoflavonol F and Glyasperin A, which had docking score of -9 kcal/mol and -8.2 kcal/mol, respectively. This indicates that both compounds are capable of being used as FBPase inhibitors for the treatment of diabetes mellitus.
Allosteric inhibition; Diabetes mellitus; Fructose 1,6-Bisphosphatase; Molecular docking; Propolis
Diabetes mellitus is a world-wide metabolic disease that is characterized by hyperglycemia, which is usually caused by insulin secretion deficiency (Association, 2014; Abdillah and Suwarno, 2016). In severe hyperglycemia cases, the disease is worsened by the accompaniment of organ failures (Association, 2014; Seeberger and Rademacher, 2014). Among several classifications of the disease, type 2 diabetes mellitus (T2DM), for which insulin resistance is an additional symptom, is accounted for 90–95% of the total recorded cases. Most T2DM patients frequently go undiagnosed for many years, and the risk increases with age, obesity, and an unhealthy lifestyle (Moller, 2001; Association, 2014; Control, 2020). To date, several T2DM drugs have been developed and marketed, including thiazolidinediones and metformin groups. Unfortunately, the use of thiazolidinediones correlates with heart failure formation while metformin has the potential to produce lactic acidosis in its users (Singh et al., 2007; Lalau, 2010). Because hyperglycemia is a major characteristic of diabetes, recently administered therapies have worked to lower patients' blood sugar levels. Several drugs have been developed and marketed with different targets and mechanism of actions (Moller, 2001; Seeberger and Rademacher, 2014). One technique that shows a promising effect is to reducing the production of endogenous glucose in the gluconeogenesis pathway which is considered as the major contributor to high blood glucose levels (Seeberger and Rademacher, 2014).
Fructose 1,6-Bisphosphatase (FBPase) is known to be the penultimate enzyme in the gluconeogenesis pathway that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate by controlling the conversion of all substrates into glucose (Erion et al., 2005; Tsukada et al., 2009; Seeberger and Rademacher, 2014). Two reasons for choosing FBPase as an inhibition target are, that: (1) it does not directly involved in glycogenolysis, glycolysis, or the tricarboxylic acid cycle (Erion et al., 2005); and (2) the genetic deficiency of the compound in humans shows no severe anomaly in biochemical and clinical parameters (Matsuura et al., 2002; Seeberger and Rademacher, 2014). In regulating blood glucose levels, the inactive state of FBPase is naturally inhibited by AMP at the allosteric site, and by fructose 2,6-bisphosphate at the substrate part (Tsukada et al., 2009). This study focuses on the allosteric site, since its nature is not highly hydrophilic, unlike that of the substrate (Erion et al., 2005).
Propolis is a resinous material collected by honeybee from various plant, which has been preclinically proven for its variety of chemical constituent, exhibiting a wide range of biological activities, including antioxidant, antimicrobial, anti-inflammatory, and antidiabetic (Fuliang et al., 2005; Diva et al., 2019; Pratami et al., 2019). Propolis constituents include polyphenols, aromatic acids, terpenoids, steroids, and amino acids depending on its vegetation and geographical origin (Kumazawa et al., 2004; Miyata et al., 2020). Propolis has been shown to have antidiabetic properties in that it reduces the total cholesterol levels, decreases low and increases high-density lipoproteins, and regulates blood glucose levels (Fuliang et al., 2005). According to Miyata et al. (2020) there are several new compounds that have been obtained from South Sulawesi propolis through X-ray structure analysis (Miyata et al., 2020).
In modern drug discovery, virtual screening of constituents has become an important step in evaluating and reducing the number of compounds to be subjected to experimental testing (Seeliger and de Groot, 2010). There are two common methods of virtual screening in drug discovery: (1) molecular docking, which simulates small molecules to protein binding sites by assuming the receptor to be rigid and have a constant covalent length and angles, as well as a rotatable ligand bond (Trott and Olson, 2010); and (2) molecular dynamics, which evaluates every single atom during simulation. This technique, however, requires many processes and high-performance hardware (Suhartanto et al., 2018). In general, docking programs use a scoring function based on empirical free binding energies to measure conformation (Trott and Olson, 2010; Forli et al., 2016). Despite the fact that there is no scoring function that accurately measures binding affinity, due to its simplification and insufficient experimental data, fitness accuracy is reached by employing optimizers, such as those used in AutoDock (Trott and Olson, 2010; Seeberger and Rademacher, 2014).
This research aims to evaluate the antidiabetic activity of South Sulawesi propolis compounds from LC-MS/MS analysis and results published by Miyata et al. (2020) by inhibiting fructose 1,6-bisphosphatase at the allosteric site. Although there have been many molecular docking studies, the use of South Sulawesi propolis as a drug candidate for diabetes mellitus has not been carried out. Therefore, this study is recommended as a reference for further in vitro research.
In this study, the in silico antidiabetic activity of South Sulawesi propolis was investigated. Among 30 selected propolis compounds, only 18 showed promising docking scores compared to AMP (-6.7 kcal/mol). Meanwhile, Broussoflavonol F and Glyasperin A showed docking scores of -9 kcal/mol and -8.2 kcal/mol, respectively, indicating 100% residue similarity in its interaction compared to the two re-docked positive controls and the AMP reference. Thus, both compounds have the potential to act against T2DM by inhibiting FBPase. Furthermore, the flavonoid structure is recommended for designing FBPase inhibitors. Finally, to ensure the validity of this finding, further research should be conducted by employing in vitro studies.
We acknowledge the financial support from the Ministry of Research, Technology, and Higher Education Republic of Indonesia through the Grants Penelitian Tesis Magister (Nomor:8/E1/KP.PTNBH/2020 and Nomor:255/PKS/R/UI/2020).
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