http://ejurnal.
id/index.
php/photon Innovation of Areca catechu Compounds Combined with Fluoxetine as Antidepressant by In Silico Method Riryn Novianty*.
Rexi Dwi Wardana.
Ulya Putri Ningsih.
Rahmad Setiawan Rabb Department of Chemistry.
Faculty of Mathematics and Natural Sciences.
Universitas Riau.
Kampus Bina Widya.
Jl.
HR Soebrantas Km 12,5.
Pekanbaru 28293.
Riau.
Indonesia *Correspondence e-mail: rirynnovianty@lecturer.
Abstract Depression is a mental illness that has become a common problem worldwide with more than 300 million cases.
The study aimed to determine the effectiveness of natural compound modification with synthetic compounds as new antidepressant drug candidates.
The method used in the research is In Silico approach using ChemSketch software.
BIOVIA Discovery Studio Visualizer (DSV), and Autodock Vina.
The bond-free energy result from a combination of arecoline, homoarecoline and guvacoline with fluoxetine on 2Z5Y protein were -7.
1 kcal/mol.
1 kcal/mol and -7.
6 kcal/mol, respectively.
Meanwhile, in 2NW8 protein, the bond free energy observed were -6.
3 kcal/mol.
3 kcal/mol, and -8.
8 kcal/mol, respectively.
Based on bond-free energy data, the additive interaction of arecoline-fluoxetine and fluoxetine-homoarecoline on MAO-A protein .
Z5Y) was barely different from fluoxetine itself.
Meanwhile, the additive interaction of guvacoline-fluoxetine was better with serotonin precursor protein .
NW.
rather than MAO-A protein .
Z5Y).
Keywords: Antidepressants, arecoline, fluoxetine, guvacoline, homoarecoline Abstrak Depresi merupakan penyakit mental yang telah menjadi masalah umum di seluruh dunia dengan lebih dari 300 juta kasus.
Penelitian ini bertujuan untuk mengetahui efektivitas modifikasi senyawa alami dengan senyawa sintetik sebagai kandidat obat antidepresan baru.
Metode yang digunakan dalam penelitian adalah pendekatan secara In Silico dengan menggunakan software ChemSketch.
BIOVIA Discovery Studio Visualizer (DSV), dan Autodock Vina.
Energi bebas ikatan yang dihasilkan dari kombinasi arekolin, homoarekolin dan guvakolin dengan fluoksetin pada protein 2Z5Y adalah -7,1 kkal/mol.
-7,1
kkal/mol dan -7,6 kkal/mol.
Sedangkan pada protein 2NW8, energi bebas ikatan yang teramati adalah -6,3 kkal/mol.
-6,3
kkal/mol, dan -8,8 kkal/mol.
Berdasarkan data energi bebas ikatan, interaksi aditif arekolin-fluoksetin dan homoarekolinfluoksetin pada protein MAO-A .
Z5Y) hampir tidak berbeda dengan fluoksetin itu sendiri.
Sementara itu, interaksi aditif guvakolin-fluoksetin lebih baik dengan protein prekursor serotonin .
NW.
daripada protein MAO-A .
Z5Y).
Kata kunci: Antidepresan, arekolin, fluoksetin, guvakolin, homoarekolin Introduction Depression is a mental disorder marked by unstable emotions, difficulty concentrating, a lack of interest in exciting things, physical disturbances .
ifficulty sleeping and eatin.
, pessimistic thinking, and suicidal Depression has become a common disease problem around the world, affecting over 350 million people (Aldahmashi et al.
In Indonesia, as many as 1522 people suffered from depression as a result of the COVID-19 pandemic (Zahroh et al.
Neurotransmitters such as serotonin, dopamine, and noradrenaline play an important role in mood, desire, and emotion, even influencing impulse control (Margret et al.
Depression can be treated using Synthetic drugs like Fluoxetine.
Fluoxetine (SSRI) is typically used for people suffering from depression to raise serotonin levels (Kaur et al.
However, fluoxetine has side effects such as sweating, asthenia, insomnia, diaphoresis, tremor, sexual dysfunction, increased risk of bleeding, and dry mouth (Tarleton et al.
In Malay culture, areca nuts are always used in a traditional event called "menginang".
The combination of synthetic drugs and herbal plants has been carried out by in vivo, but the mechanism of the additive interaction is unknown (Kaur et al.
In silico approach possibly solves this Previously, in silico studies to predict drug candidates as antidepressants have been carried out with Swiss ADME analysis, molecular docking (Sirait and Novianty 2022.
Ningsih and Novianty 2020.
Maylinda Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon and Novianty 2021.
Riryn Novianty 2.
, and molecular dynamics simulations (Ananta and Novianty 2022.
The molecular docking of fluoxetine with the areca nutAos active compound is a novel feature of this research.
Areca nut has a few active compounds such as arecoline, homoarecoline, and guvacoline which can be used as oral drugs (Peng et al.
Furthermore, the most appropriate strategy for designing an antidepressant is to inhibit the Mnoamine oxidase A (MAO-A) enzyme because it will increase the concentration of neurotransmitter (Chu 2001.
Stahl Furthermore, these compounds of Areca nut can inhibit MAO-A activity by in vivo (Ramsay 2013.
Boucher and Mannan 2.
Various studies included behavioural in animal .
cute and sub-chronic forced swim test.
anf biochemical (MAO-A and their metabolite levels using high performance liquid chromatograph.
are done to look into the potential antidepressant efficacy of Areca nut ethanol extract and its various fractions (Dar and Khatoon 1.
Recently, in silico approach using natural compounds has been carried out (Novianty et al.
However, in silico study about a combination of synthetic drugs and natural compounds has not been Therefore, this study was conducted to determine the effectiveness of areca nutAos active compounds combined with fluoxetine as a recent antidepressant drug Methods Materials and Instrumentals Bahan This study was conducted by molecular docking method using a laptop (ASUS IntelA core i3-7020Li, 3 GHz.
RAM 4.
00 GB).
The software used in this study are ChemDraw Ultra 13.
ChemSketch.
AutoDock Vina, and BIOVIA Discovery Studio Visualizer (DSV).
MAO-A target protein .
Z5Y) and serotonine precursor .
NW.
, areca nutAos chemical formula .
recoline, guvacoline dan homoarecolin.
and fluoxetine chemical formula was obtained from protein data bank.
Experimental Procedure Synthesis reaction of areca nutAos compound and fluoxetine The synthesis reaction was drawn using ChemSketch software.
The reactions obtained from the combination of compounds shown below.
Figure 1.
The chemical reaction of Arecoline with Fluoxetine (Code: AF) Figure 2.
The chemical reaction of Homoarecoline with Fluoxetine (Code: HF) Figure 3.
The chemical reaction of Guvacoline with Fluoxetine (Code: GF) Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon Validation of redocking on native protein .
Z5Y dan 2NW.
The 3D structure of 2Z5Y protein (MAO-A protei.
and 2NW8 protein .
erotonin precurso.
was validated by redocking using DSV.
Water molecules and other molecules bound to the original protein as well as the native ligands of the protein are removed, and the file is saved in Au.
pdbAy format.
Subsequently, the original ligand is processed by eliminating the protein and other molecules from the native protein.
Furthermore, the original ligand is saved in the form of Au.
pdbAy format.
Protein and ligand preparation The molecular structure of the combination compound with codes AF.
HF, and GF was drawn using ChemDraw Ultra 13.
0 and saved in Auprotein data bankAy format.
The protein structure was downloaded from the org website in PDB format (PDB ID: 2Z5Y), then water molecules and initial ligands on the protein were eliminated and the determination of the active site of the 2Z5Y receptor using DSV.
The same is done with protein 2NW8.
Docking simulation via Autodock Vina Before doing the docking simulation, it is necessary to prepare AF.
HF and GF ligands by increasing 6x torsion tree and saving them in .
pdbqt format.
The same is done with fluoxetine.
Receptor preparation was carried out by validating and dismissing all protein components .
ative ligands and water molecule.
Hydrogen is added and make a the receptor in a polar condition.
Files are saved in AupdbqtAy format.
Next, a grid box is done by setting the grid spacing to 1 yI and the grid points x, y, z are arranged so that they can contain the active protein site.
Grid point on protein 2Z5Y, are x = 104.
y = 96 and z = 74.
Whereas in 2NW8 protein, position x = 68.
y = 84 and z = 84.
The docking procedure is claimed valid because from 3 docking experiments, the same value is obtained (Purwaniati 2.
Data Analysis The docking result was interpreted via command prompt application with AuC:\Vina>Vina Aeconfig config.
txt Ae log log.
txtAy settings.
Then, press enter.
So, the docking result will interpret in the command prompt and automatically saved in Auoutput.
pdbqtAyformat Hasil dan Pembahasan Molecular Docking Between Fluoxetine and Areca Nut Compounds with MAO-A Protein Ligands Fluoxetine AF and HF Table 1.
Molecular docking result of ligands with MAO-A Binding Affinity Hydrophobic and Hydrogen Bonding .
cal/mo.
Van Der Waals Interactions MET445.
SER24.
TYR69.
TYR444.
GLY443.
THR435.
ILE23.
THR52.
ALA448.
GLY22.
GLY66.
ARG51.
CYS406
GLY67.
TYR407
THR 205
PHE112.
PRO114.
ALA110,
HIS488.
TYR124.
ASN125,
TYR204.
TRP128
ALA 44
VAL244.
THR24.
GLY21,
GLU43.
TYR402.
GLY20,
LYS280.
ILE273.
TYR402,
LEU277
The result of molecular docking of ligands with MAO-A .
ZY) protein are shown in Table.
It was found that fluoxetine has a bond free energy value of -9.
1 kcal/mol and RMSD value of 0.
The docking results showed that fluoxetine could bind to 15 amino acid residues on the active site of the receptor, namely MET445.
SER24.
THR435.
ILE23.
ARG51.
CYS406.
TYR69.
TYR444.
GLY443.
THR52.
ALA448.
GLY22.
GLY66.
GLY67.
TYR407.
Fluoxetine interacts with receptors via hydrogen bonding with MET445.
SER24.
THR435.
ILE23.
ARG51.
CYS406 residues.
Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon The drug effectiveness was observed from its bond free energy and RMSD value.
Bond free energy is the energy required for initiating intermolecular interactions and complex formation between ligands and The bond free energy expresses the amount of a ligand bound to the receptor.
If the bond free energy value is small, then the bond is stronger.
Meanwhile if the bond free energy value is large, the bond is getting weaker and possible to break the loose (Weni et al.
The difference from the bond-free energy value is based on the protein residue that interacts with the ligand.
RMSD used to measure the difference between the predicted value and the observation value.
The RMSD value is said to be good if O 2 yI (Kumer et 2.
If the deviation bigger, then the prediction error is bigger too.
So, the best bond free energy value from the bonding results of each ligand is the one that has an RMSD value = 0.
The combination of AF (Arecoline fluoxetin.
and HF (Homoarecoline fluoxetin.
has a bond free energy value -7.
1 kcal/mol and RMSD value 0.
The docking results showed that the combination of AF and HF did not bind to amino acid residues on the receptorAos active site.
The combination of AF and HF interacts with receptor via hydrogen bonding with THR205 amino acid residue.
The combination of GF (Guvacoline fluoxetin.
has a bond free energy value -7.
6 kcal/mol and an RMSD value of 0.
The docking results showed that the GF combination did not bind to the amino acid residue on the receptorAos active site.
Combination of GF interacts with receptor via hydrogen bonding with ALA44 amino acid residue.
Figure 4.
3D Visualization of Interaction between AF and HF with Amino Acid Residue in 2Z5Y Protein Figure 5.
2D Visualization of Interaction between AF and HF with Amino Acid Residue in 2Z5Y Protein The drug-receptor bond interaction based on the results of 3D and 2D visualization of MAO-A protein which illustrated in Figure 4 and Figure 5 with AF and HF compounds consisting of hydrogen bonds (THR.
, van der walls bonds (THR.
, phi-anionic bonds (GLU.
C-H bonds (PHE.
, pi-pi T-shaped bonds (TYR124 and TRP.
, alkyl activators (ALA110 and PRO.
and pi-alkyl bonds (HIS.
Meanwhile, in GF compounds (Figure 6 and Figure .
, there are hydrogen bond interactions (ALA.
, van der Walls bonds (VAL244.
THR245 and GLY.
, halogen bonds (GLU.
, pi-sigma bonds (TYR.
C-H bonds (GLY20.
LYS.
, phi-sigma bonds (ILE.
, pi-pi T-shaped bonds (TYR.
, alkyl bonds (LEU.
Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon Figure 6.
3D Visualization of Interaction between GF with Amino Acid Residue in 2Z5Y Protein Figure 7.
2D Visualization of Interaction between GF with Amino Acid Residue in 2Z5Y Protein Molecular Docking Between Fluoxetine and Areca Nut Compounds with Serotonin Precursors Ligands Fluoxetine Table 2.
Molecular docking result of ligands with Serotonin Binding Affinity Hydrophobic and Hydrogen Bonding .
cal/mo.
Van Der Waals Interactions Ser 123 LEU 263.
VAL 244.
LEU
THR 243.
VAL 247,
PHE 51.
TYR 113.
ILE
GLY 125.
LEU 108.
LEU 120,
SER124.
THR 254.
GLY 253,SER
AF and HF TYR 113.
ILE 248.
PHE
VAL 247.
VAL 244,
LEU 263.
SER 124.
SER
GLY 253.
SER 257.
VAL
TYR 113.
ILE 248,
VAL 247.
PHE 51.
LEU
LEU 108.
THR 243,
SER 124.
GLY 125
The result of molecular docking of ligands with Serotonin .
NW.
protein are shown in Table 2.
Based on the Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon docking result between antidepressant compounds and serotonin precursors, it was found that fluoxetine has a bond-free energy value of -8.
5 kcal/mol and an RMSD value of 0.
The docking results showed that fluoxetine could bind to 16 amino acid residues on the receptorAos active site, namely LEU263.
VAL244.
LEU105.
THR243.
VAL247.
PHE51.
TYR113.
ILE248.
GLY125.
LEU108.
SER123.
LEU120.
SER124.
THR254.
GLY253.
SER257.
Fluoxetine interacts with the receptor via hydrogen bonding with the SER123 amino acid The combination of AF (Arecoline fluoxetin.
and HF (Homoarecoline fluoxetin.
has a bond-free energy value of -6.
3 kcal/mol and an RMSD value of 0.
The docking results showed that the combination of AF and HF binds to 8 amino acid residues on the receptorAos active site, namely TYR113.
ILE248.
PHE51.
VAL247.
VAL244.
LEU263.
SER124.
SER123.
The combination of AF and HF does not interact with the receptor via hydrogen bonding.
The combination of GF (Guvacoline fluoxetin.
has a bond-free energy value of -8.
kcal/mol and an RMSD value of 0.
The docking results showed that the combination of GF binds to 11 amino acid residues on the receptorAos active site, namely GLY253.
SER257.
VAL244.
TYR113.
ILE248.
VAL247.
PHE51.
LEU105.
LEU108.
THR243.
SER124.
GLY125.
Figure 8.
3D Visualization of Interaction between AF and HF with Amino Acid Residue in 2NW8 Protein Figure 9.
2D Visualization of Interaction between AF and HF with Amino Acid Residue in 2NW8 Protein According to the 3D and 2D visualization of the serotonin precursor protein in Figure 8 and Figure 9 with the combination compound AF.
HF and GF, there is no hydrogen bond.
Molecular interactions on the ligand receptor are not only through hydrogen bonds but also through electrostatic interactions and hydrophobic interactions that contribute to the value of the bond energy (OIG ligand-recepto.
(Arwansyah et The interaction contained in the combination of AF and HF compounds with serotonin precursor proteins, namely van der Walls bonds (ARG117.
GLY259.
ILE248.
LEU263.
SER.
C-H bonds (SER124 and TYR.
, pi-sigma bonds (VAL.
, alkyl bonds (VAL247 and LEU.
Received: 3 Mei 2023.
Accepted: 20 Mei 2023 - Jurnal Photon Vol.
13 No.
DOI: https://doi.
org/10.
37859/jp.
PHOTON is licensed under a Creative Commons Attribution-ShareAlike 4.
0 International License http://ejurnal.
id/index.
php/photon Figure 10.
3D Visualization of Interaction between GF with Amino Acid Residue in 2NW8 Protein Figure 11.
2D Visualization of Interaction between GF with Amino Acid Residue in 2NW8 Protein Meanwhile, in GF combination compounds (Figure 10 and Figure .
there are van der Walls bonds (PHE126.
PHE262.
GLY253.
GLY255.
LEU108.
THR243.
SER124.
GLY259.
LEU263.
GLY125.
HIS.
C-H bonds and pi-donor hydrogen bonds (SER257 and TYR.
, and alkyl bonds (VAL244.
ILE248.
PHE51.
LEU.
Conclusion Based on the interaction of antidepressant compounds with MAO-A protein, fluoxetine has the smallest binding free energy value compared to AF.
HF and GF compounds.
It indicates that fluoxetine is more effective than the AF.
HF and GF.
Meanwhile, in the interaction of antidepressant compounds with serotonin precursors.
GF compound has the smallest bond free energy value compared to AF.
HF and fluoxetine.
indicates that GF is more effective than AF.
HF and fluoxetine.
References