INTRODUCTION:

One of metabolic disorder was diabetes caused by hyperglycemia condition. There were 2 type of diabetes such as type 1 and 2. Type 1 diabetes was caused by pancreas damage, so it could not produce insulin, and type 2 by impairing in insulin signaling, so the activity of glucose transportation was inhibited and glucose couldn’t enter to the cell, so glucose was still in circulation and caused hyperglycemia. Hyperglycemia might cause damage in many organ system. Insulin signaling could be impaired by increasing of Reactive Oxygen Species (ROS) in obesity condition. Obesity was characterized by excessive fat accumulation in abdomen, abdominal fat could be visceral fat and subcutaneous fat¹.

Fat accumulated in adipose tissue, then adipose tissue released increased amounts of fatty acid and proinflammatory cytokines (TNF-α, IL-6 and IL-8) to circulation that were involved in impairing insulin signaling and caused insulin resistance².

Proinflammatory cytokines binded to its receptor then induced JNK (c-Jun N-terminal kinase) activity to inhibit IRS1 (Insulin receptor substrat I) activity and then inhibit the activity of GLTU 4 (Glucose Transporter 4). Then it would impair insulin signaling³. Actually IRS1 would induce PI3K that induced Phosphorilation of Akt/PKB (Protein Kinase B) to induce the movement of GLTU 4 to cell membrane. GLTU4 would make glucose enter to the cell. If inflammatory factor increased, the effect was decreasing glucose in cells, but increasing glucose in circulation⁴.

The use of medicinal plants is widely used for the prevention of diabetes. On of medicinal plants was Daun Wungu (Graptophyllum pictum L. Griff)⁵. Daun Wungu ethanol extract contained some active compounds such as 6-Octadecenoic acid, 8-Octadecenoic acid, 9-Octadecenoic acid, Coumaran-5,6-Diol-3-One, 4H-1-Benzopyran-4-one, 1,2-Benzisothiazol-3-amine, Quinoline, 6-(4,5-diphenylimidazol-2-yl), As-Indacen-1(2H)-one, 2,4-Cyclohexadien-1-one, 1,4-Phthalazinedione, Benzo[h]quinoline, Thymol, Phytol, Phenol, and Galangin^6,7. This reseach was aimed to know the effect of Daun Wungu (Graptophyllum pictum L. Griff) ethanol extract to prevent type 2 diabetes by inhibiting the activity of proinflammatory factor (TNF-α, IL- 6 and IL- 8). If all of active compound could bind to TNF-α, IL- 6 and IL- 8, so proinflammatory factor would be inhibited to its receptor and the activity was inhibited.

MATERIAL AND METHODS:

Ligand-protein preparation:

The 3D structure of chemical compounds from Daun Wungu (Graptophyllum pictum L. Griff) in this study consisted of 6-Octadecenoic acid, 8-Octadecenoic acid, 9-Octadecenoic acid, Coumaran-5,6-Diol-3-One, 4H-1-Benzopyran-4-one, 1,2-Benzisothiazole-3-amine, Quinoline, 6-(4,5-diphenylimidazole-2-yl), As-Indacen-1(2H)-one, 2,4-Cyclohexadien-1-one, 1,4-Phthalazinedione, Benzo[h]quinoline, Thymol, Phytol, Phenol, and Galangin were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/). PubChem includes a specific database whose role is to store all information about natural, synthetic, and substance^8,9. This study used TNF-α, IL-6, and IL-8 as targets and obtained from the Protein Databank (https://www.rcsb.org/). PyMol 2.5 version software is used for the sterilization process of 3D protein samples, then the OpenBabel plug in PyRx 0.9.9 version software is used for ligand file format conversion and increased flexibility through energy minimization^10,11.

Druglikeness prediction:

Druglikeness is a qualitative test that is used to determine the level of similarity of natural ingredients compounds with the performance of drug molecules through several specific parameters^12,13. Druglikeness in this study was carried out through the SwissADME server (http://www.swissadme.ch/), this prediction aims to determine the general physicochemical characteristics and performance of query compounds as drug-like molecules based on various test parameters such as Lipinski, Ghose, Veber, Egan, Muegge, and Bioavailability^14,15. In addition, the druglikeness analysis is also used for this purpose, which aims to determine the activity and mode of action of query compounds when interacting with target cells^16,17.

Molecular docking analysis:

The simulation of ligand binding to the target was carried out using molecular docking software on the VinaWizard plugin in PyRx 0.9.9 version. The simulation aims to determine the level of binding ability of a ligand to the protein domain based on the binding affinity value of the ligand-protein stable complex and generate negative energy¹⁸. The ligands in this study were all compounds from Daun Wungu and then TNF-α, IL-6, and IL-8 proteins acted as targets. The docked 3D structure is displayed with cartoons, surfaces, and sticks structures using PyMol 2.5 version software¹⁹.

Ligand-protein interactions:

The molecular complex as a result of the docking analysis identified the positions and types of chemical bond interactions formed through the Discovery Studio 2016 version software. Weak bonds formed in ligand and protein complexes can affect specific biological activities, the types of chemical bonds formed consist of hydrogen, hydrophobic, pi, and electrostatic. So the more interactions that are formed, it is possible for a ligand to affect the activity of the target protein²⁰.

Molecular dynamic simulation:

The stability of the ligand based on the root mean square fluctuation (RMSF) of amino acids in the binding domain was identified through molecular dynamic simulation analysis with the CABS-flex 2.0 version server (http://biocomp.chem.uw.edu.pl/CABSflex2). This prediction refers to the parameters of protein restrants, rigidity, C-alpha, side-chain, number of cycles, trajectory, temperature range, and RNG seed. Ligands are stable if they have an RMSF value of not more than 4^21,22.

RESULT AND DISCUSSION:

Chemical compounds from Daun Wungu (Graptophyllum pictum L. Griff) consisting of 6-Octadecenoic acid (CID 5282754) 8-Octadecenoic acid (CID 5282758), 9-Octadecenoic acid (CID 637517) Coumaran-5,6-Diol-3-One (CID 313095), 4H -1-Benzopyran-4-one (CID 10286), 1,2-Benzisothiazol-3-amine (CID 89966), Quinoline, 6-(4,5-diphenylimidazole-2-yl) (CID 631489), As-Indacen-1(2H)-one (CID 611673), 2,4-Cyclohexadien-1-one (CID 141125), 1,4-Phthalazinedione (CID 283593), Benzo[h]quinoline (CID 9191), Thymol (CID 6989 ), Phytol (CID 5280435), Phenol (CID 996), and Galangin (CID 5281616) were obtained from the PubChem database with information, CID numbers and 3D structures. The 3D structure of the target protein consisting of TNF-α (PDB ID: 1TNF), IL-6 (PDB ID: 1ALU), IL-8 (PDB ID: 1IL8) was obtained from the RCSB PDB database with ID and samples in pdb format. The 3D structure of the target ligand and protein is displayed using PyMol 2.5 version software in the form of sticks, cartoons, spheres, and transparent surfaces with coloring selection based on the type of molecule are presented in Figure 1.

Figure 1. Visualisasi 3D ligan dan protein. (A) 6-Octadecenoic acid (B) 8-Octadecenoic acid (C) 9-Octadecenoic acid (D) Coumaran-5,6-Diol-3-One (E) 4H-1-Benzopyran-4-one (F) 1,2-Benzisothiazol-3-amine (G) Quinoline, 6-(4,5-diphenylimidazol-2-yl) (H) As-Indacen-1(2H)-one (I) 2,4-Cyclohexadien-1-one (J) 1,4-Phthalazinedione (K) Benzo[h]quinoline (L) Thymol (N) Phytol (M) Phenol (O) Galangin (P) TNF-α (Q) IL-6 (R) IL-8.

Druglikeness is a qualitative analysis that is used to determine the level of similarity of natural ingredients compounds with the performance of drug molecules through several specific parameters such as physicochemical properties and probability tests with specific parameters²³. The physicochemical properties of the compounds containing Daun Wungu (Graptophyllum pictum L. Griff) as predicted by the Swiss ADME server were identified according to the formula, weight, heavy atoms, fraction csp3, hydrogen bonds between acceptors and donors, molar refractivity, total polar surface area (TPSA) are presented in Table 1. Parameters on physicochemical properties can be used for additional data in the prediction of druglikeness. The results of the identification of drug-like molecules based on the parameters of Lipinski, Ghose, Veber, Egan, Muegge, and the value of bioavailability, all compounds containing Daun Wungu are predicted to work as drug-like molecules are presented in Table 2. Compounds that are included in the drug-like molecule category can generally affect the activity of the target protein but the exact binding mechanism is not known²⁴.

Table 1. Physicochemical properties of Daun Wungu compounds.

Compounds	Formula	Weight (g/mol)	Heavy Atoms	Fraction Csp3	Rotatable Bonds	H Acceptors	H Donors	Molar Refractivity	TPSA (Å²)
6-Octadecenoic acid	C18H34O2	282.46	20	0.83	15	2	1	89.94	37.30
8-Octadecenoic acid	C18H34O2	282.46	20	0.83	15	2	1	89.94	37.30
9-Octadecenoic acid	C18H34O2	282.46	20	0.83	15	2	1	89.94	37.30
Coumaran-5,6-Diol-3-One	C8H6O4	166.13	12	0.12	0	4	2	40.25	66.76
4H-1-Benzopyran-4-one	C9H6O2	146.14	11	0.00	0	2	0	42.48	30.21
1,2-Benzisothiazol-3-amine	C7H6N2S	150.20	10	0.00	0	1	1	44.02	67.15
Quinoline, 6-(4,5-diphenylimidazol-2-yl)	C24H17N3	347.41	27	0.00	3	2	1	110.20	41.57
As-Indacen-1(2H)-one	C16H20O	228.33	17	0.56	0	1	0	71.11	17.07
2,4-Cyclohexadien-1-one	C6H6O	94.11	7	0.17	0	1	0	28.09	17.07
1,4-Phthalazinedione	C8H4N2O2	160.13	12	0.00	0	4	0	46.61	58.86
Benzo[h]quinoline	C13H9N	179.22	14	0.00	0	1	0	59.25	12.89
Thymol	C10H14O	150.22	11	0.40	1	1	1	48.01	20.23
Phytol	C20H40O	296.53	21	0.90	13	1	1	98.94	20.23
Phenol	C6H6O	94.11	7	0.00	0	1	1	28.46	20.23
Galangin	C15H10O5	270.24	20	0.00	1	5	3	73.99	90.90

Table 2. Drug-like molecule prediction of Daun Wungu compounds.

Compounds	Lipinski	Ghose	Veber	Egan	Muegge	Bioavailability	Probability
6-Octadecenoic acid	Yes	No	No	No	No	0.85	Drug-like molecule
8-Octadecenoic acid	Yes	No	No	No	No	0.85	Drug-like molecule
9-Octadecenoic acid	Yes	No	No	No	No	0.85	Drug-like molecule
Coumaran-5,6-Diol-3-One	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
4H-1-Benzopyran-4-one	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
1,2-Benzisothiazol-3-amine	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
Quinoline, 6-(4,5-diphenylimidazol-2-yl)	Yes	No	Yes	No	No	0.55	Drug-like molecule
As-Indacen-1(2H)-one	Yes	Yes	Yes	Yes	No	0.55	Drug-like molecule
2,4-Cyclohexadien-1-one	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
1,4-Phthalazinedione	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
Benzo[h]quinoline	Yes	Yes	Yes	Yes	No	0.55	Drug-like molecule
Thymol	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
Phytol	Yes	No	No	No	No	0.55	Drug-like molecule
Phenol	Yes	No	Yes	Yes	No	0.55	Drug-like molecule
Galangin	Yes	Yes	Yes	Yes	Yes	0.55	Drug-like molecule

Prediction of ligand binding mechanism with protein can be done through molecular docking simulation, this research uses PyRx 0.9.9 version software for docking. The simulation aims to determine the level of binding ability of a ligand to the protein domain based on the binding affinity value of the ligand-protein stable complex and generate negative energy. Binding affinity is formed when there is an interaction between protein and ligand, this energy is formed through a reversible reaction at constant temperature and pressure according to the laws of thermodynamics²⁵. The grid in the docking simulation plays a role in directing the binding of the ligand to the proteins²⁶. This study used a grid arrangement on different target, namely TNF-α Center (Å) X: 19,968 Y: 49,675 Z: 39,930, Dimension (Å) X: 80,739 Y: 58,243 Z: 58,256, IL-6 Center (Å) X: 2,675 Y: -20,084 Z: 8,908, Dimension (Å) X: 58.092 Y: 62.897 Z: 43139, and IL-8 Center (Å) X: -0.859 Y: -7.374 Z: 1.905 Dimension (Å) X: 63,313 Y: 56,673 Z: 52,220.

The docking simulation in this study aims to identify the comparison of the binding activity of compounds containing in Daun Wungu (Graptophyllum pictum L. Griff) on the three proteins. The docking simulation results that Quinoline, 6-(4,5-diphenylimidazole-2-yl) has the most negative binding affinity value for all target proteins, namely TNF-α, IL-6, and IL-8 are presented in Table 3. Quinoline, 6-(4,5-diphenylimidazole-2-yl) is predicted to have a stronger binding energy than other compounds in Daun Wungu (Graptophyllum pictum L. Griff) and has the potential to affect the biological activity of the three target proteins. Visualization of the molecular complex docking of Quinoline, 6-(4,5-diphenylimidazole-2-yl) with TNF-α, IL-6, and IL-8 displayed in transparent surfaces, cartoons, and sticks structures are presented in Figure 2.

Table 3. The result of molecular docking of all compounds contained in Daun Wungu (Graptophyllum pictum L. Griff) leaf with TNF-α, IL-6 and IL-8.

Compounds	Binding Affinity (kcal/mol)
Compounds	TNF-α	IL-6	IL-8
6-Octadecenoic acid	-3.7	-4.7	-4.1
8-Octadecenoic acid	-5.5	-4.2	-4.1
9-Octadecenoic acid	-5.1	-4.5	-4.2
Coumaran-5,6-Diol-3-One	-6.5	-5.5	-4.8
4H-1-Benzopyran-4-one	-6.4	-5.2	-4.9
1,2-Benzisothiazol-3-amine	-5.6	-5.1	-4.7
Quinoline, 6-(4,5-diphenylimidazol-2-yl)	-9.0	-7.1	-7.6
As-Indacen-1(2H)-one	-7.8	-6.5	-6.4
2,4-Cyclohexadien-1-one	-4.7	-4.5	-4.0
1,4-Phthalazinedione	-7.0	-5.8	-5.4
Benzo[h]quinoline	-7.1	-6.2	-6.0
Thymol	-5.4	-5.0	-5.9
Phytol	-6.0	-4.4	-4.5
Phenol	-4.8	-4.5	-3.8
Galangin	-7.0	-6.2	-6.8

Figure 2. Three-dimensional structure of ligan-protein from the docking results. (A) Quinoline_TNF-α (B) Quinoline_IL-6 (C) Quinoline_IL-8.

The interaction between the ligands on the target protein occurs through weak bonds, it plays a role in triggering the activation of specific biological activity^27,28. Quinoline compound, 6-(4,5-diphenylimidazole-2-yl) interacts with TNF- via positions Glu104, Gln102, Arg103, Glu104, Gln102, Cys101, and Pro100 with Van der Waals bonds, Pi bonds on Arg103 and Arg103, and hydrogen bonds at Gln102, at IL-6 via positions Glu106, Glu105, Glu42, Thr43, Gln156, Trp157, and Ser47 with Van der Waals bonds, Pi bonds at Asp160 and Arg104, and hydrogen bonds at Glu42, at IL-8 via the positions of Val58, Pro53, Glu70, Glu63, Gln59, and Glu70 with Van der Waals bonds, Pi bonds on Ile39, Val62, Gln59, Leu66, and Lys67 and hydrogen bonds on Glu63, then there are two unfavorable bonds formed on the N atoms that make up the query ligand are presented in Figure 3.

Figure 3. Two-dimensional visualization of ligan-protein interaction. (A) Quinoline_TNF-α (B) Quinoline_IL-6 (C) Quinoline_IL-8.

The validation of the docking results can be done through molecular dynamic simulations, it aims to determine the stability of the molecular complex formed^29,30. The results of the molecular dynamic simulation analysis showed that Quinoline, 6-(4,5-diphenylimidazole-2-yl) compound could bind stably to the three target proteins with a lower RMSF of about 2 – 3 are presented in Figure 4. The following is a link to the CABS-flex 2.0 version of the molecular dynamic simulation results from this research. The molecular complex resulting from docking A (http://biocomp.chem.uw.edu.pl/CABSflex2/job/f92aba06dfdb35e/), the molecular complex from docking B (http:// biocomp.chem.uw.edu.pl/ CABSflex2/job/4ab8cf38b0b6dff/), C docked molecular complex (http://biocomp.chem.uw.edu.pl/CABSflex2/job/68f9ca4101c197e/).

CONCLUSION:

Quinoline compound, 6-(4,5-diphenylimidazole-2-yl) contained in Daun Wungu (Graptophyllum pictum L. Griff) had a stronger binding energy to the target protein than others. The compound was predicted to trigger the inhibition of the activity of TNF- α, IL-6, and IL-8 proteins better because it could produce more negative binding energy, stronger bond interactions, and produce stable molecular complexes, but the results of this study still had to undergo further testing through in vitro and in vivo approaches to strengthen the evidence base.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest regarding the publication of this article.

ACKNOWLEDGMENTS

This work was supported by Universitas Airlangga.

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Received on 11.05.2022 Modified on 02.08.2022

Research J. Pharm. and Tech 2023; 16(5):2291-2296.

DOI: 10.52711/0974-360X.2023.00376