DFT and Molecular Docking Investigations Curcuminoid to Tribolium castaneum Telomerase Enzyme

 

Mirella F. Maahury¹, Mario R. Sohilait¹, Muhamad A. Martoprawiro², Viol D. Kharisma^3,4, Priscilla Listiyani³, Arif N. M. Ansori^5,6, Santika L. Utami⁷, Alexander P. Nugraha⁸, Imam Rosadi⁹, Riso S. Mandeli¹⁰, Muhammad A. Ghiffari¹¹,

Muhammad T. Albari¹¹, Muhammad R. Ghiffari¹¹, Rahadian Zainul^12,13*

¹Chemistry Department, Faculty Mathematics and Natural Sciences, Universitas Pattimura, Ambon, Indonesia.

²Chemistry Department, Faculty Mathematics and Natural Sciences,

Institut Teknologi Bandung, Bandung, Indonesia.

³Division of Molecular Biology and Genetics, Generasi Biologi Indonesia Foundation, Gresik, Indonesia.

⁴Doctoral Program of Mathematics and Natural Sciences, Faculty of Science and Technology,

Universitas Airlangga, Surabaya, Indonesia.

⁵Doctoral Program of Veterinary Sciences, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

⁶Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.

⁷Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia.

⁸Orthodontics Department, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

⁹Department of Biology, Faculty of Mathematics and Natural Sciences, Mulawarman Univeristy.

¹⁰Environmental Science, Postgraduate Programme, Universitas Negeri Padang, Padang, Indonesia.

¹¹Department of Informatics Engineering, Faculty of Computer Sciences,

Universitas Brawijaya, Malang, Indonesia.

¹²Center for Energy and Power Electronics Research (CEPER), Universitas Negeri Padang, Padang, Indonesia.

¹³Chemistry Department, Universitas Negeri Padang, Padang, Indonesia.

 

ABSTRACT:

The natural curcumin (Curcuminoid) is an anticancer compound. DFT and molecular docking curcuminoid to Tribolium castaneum telomerase were performed for curcumin (C), demethoxycurcumin (DC), and bisdemethoxycurcumin (BDC) in two structures, diketone (dk) and keto-enol (ke). Curcuminoid as inhibitor have optimized in gas phase used DFT/B3LYP. Optimized structure of curcuminoids conducted unplanarity for diketone and planarity for keto-enol. The HOMO-LUMO of curcuminoid spread mostly in entire molecule. Three compounds of curcuminoid could dock to active side of Tribolium castaneum telomerase. Binding energy of the diketone structure has lower energy than keto-enol structure. The binding energy of the diketone structure for the three compounds is between -7.5 to -7.7kcal/mol. This molecular docking shows intermolecular interaction between curcuminoid and active side of Tribolium castaneum telomerase dominated by hydrogen bonding. Curcuminoid diketone has potency as an inhibitor to Tribolium castaneum telomerase.

 

 

 

INTRODUCTION: 

Cancer is one of the leading caused dead in the world. The death rate from cancer increased during most of the 20th century. A cancer cell can produce and replicate because of the presence of telomerase. Telomerase has a role as a replicator in every cell replication that could maintain telomere length in its derivative cell. If cancer cells do not have enough telomerase enzymes, cancer cells' growth will stop by itself¹.Cancer treatment by inhibiting the telomerase enzyme leads to efficient healing, which only work in the cancer cell without effect, such as chemotherapy. Some in vivo investigations have been done to inhibit telomerase enzyme in the cancer cell. Kazemi et al. have successfully inhibited telomerase enzyme in the breast cancer cell with complex β-cyclodextrin curcumin. They obtain activity telomerase enzyme decrease as concentration β-cyclodextrin curcumin increases². Successfully inhibited telomerase enzyme activity with inhibitor MST-312 labeled by I123³.

 

Using synthesized medicine for cancer treatment has a high risk because it can have an effect as a poison for the other organs in the human body if the drug is consumed continuously. It also needed a lot of costs. Therefore, a drug from the natural product is more recommended because it has a low risk for body organs if consumed continuity, low cost, and uncomplicated handling. One of the drugs from the natural product is an extract from turmeric.

 

Turmeric (Curcuma longa L.) contains orange-yellow pigment in its root extract, knows as curcuminoid. Curcuminoid consists of three main compounds, namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin⁴. These three compounds equilibrium in the pentadiene chain; there are diketone and keto-enol⁵ (Figure 1). Curcuminoid in turmeric has many health benefits, such as antioxidant⁶, antitumor⁷, and antiinflamation⁸. Many researchers have investigated the extract of curcuminoid as an anticancer. Curcuminoid shows activity against cancer cells of leukemia, colon cancer, and breast cancer.

 

Figure 1 Equilibrium Structure of Curcuminoid

 

Activities against cancer cells from curcuminoids can be investigated on a molecular scale through in silico. One of in silico investigation can be performed by docking inhibitor molecule as ligand to enzyme. The aim of docking ligand to enzyme is to investigation how ligand interaction to enzyme at the molecular level and obtain how much bonding energy from these interactions. The investigation of docking curcumin as an inhibitor of several enzymes has been carried out. Sohilat, et al. analyzed the interaction of docking curcumin analogues as inhibitors to cyclooxygenase (COX-2) enzyme and found that analogous curcumin was able to inhibit COX-2 enzymes with bond energy of -8.2 to -7.5kcal/mol⁹.

 

The interaction of docking curcumin as an inhibitor of several breast cancer proteins, obtained by bonding energy of -12.1 to -8.05kcal/mol¹⁰. the potential of curcumin and methotrexate as inhibitor to dihydrofolate reductase enzyme, curcumin has a more stable bonding energy than methotrexate¹¹.  Investigation related to the interaction of inhibiting inhibitors of telomerase enzymes in silico have been carried out too. The potential of oxoisoaporphine as an inhibitor of human telomerase enzyme, obtained oxoisoaporphine has potency as an inhibitor on one side catalytic of human telomerase enzymes (hTRT)¹².

 

However, this research has its own complexity because the structure of the human telomerase enzyme has many catalytic sides making it difficult to find the interaction of ligands with the telomerase enzyme. The catalytic side of the telomerase enzyme from Tribolium castaneum which has an active side similar to the active side of human telomerase enzymes¹³. There is no investigation have been conducted to find the interaction in docking curcuminoids to the telomerase enzyme, so this research about "DFT and molecular docking investigations Curcuminoid to Tribolium castaneum tlomerase enzyme". This present research purposes to know how the interaction between curcuminoid as an inhibitor to telomerase enzyme from Tribolium castaneum.

 

METHOD:

Sample Preparation:

The ligand is curcuminoid in two structures, diketone, and keto-enol. Input construct in z-matrix form. Tribolium castaneum Telomerase enzyme is downloaded from Protein Data Bank (PDB) site. This research using PDB ID 5CQG in PDB file (.pdb)^14,15,16.

 

Geometry Optimization:

DFT calculations are performed using Gaussian 09 for LINUX, GaussView 5.08 (Gaussian. Inc). DFT was employed B3LYP functional and 6-31G(d) basis set for geometry optimization^17,18,19.

 

Molecular Docking and Visualization:

The docking are performed using AutoDock-Vina 1.1.2 (The Scripps Research Institute), Python Molecule Viewer-1.5.6 (The Scripps Research Institute), PyMol Molecular Graphic System 1.1 (DeLano Scientific LLC)^20,21,22.

 

RESULTS AND DISCUSSION:

Molecular docking study of curcuminoid as inhibitor to Tribolium castaneum telomeraseobtains some data which will be processed further to get the output that can be analyzed²³. The discussion begins with binding energy between curcuminoids and Tribolium castaneum telomerase, analysis of intermolecular interactions formed between curcuminoids and Tribolium castaneum telomerase, and closed by analyzing the interaction between curcuminoids with visualization of the output^24,25.

 

Curcuminoids naturally are in equilibrium with two structures, diketone, and keto-enol. Curcuminoid has a backbone, two phenyl rings connected by heptadiene chain.Curcuminoid diketone contains two carbonyl (C=O), located side by side and separated by methylene (-CH₂-) in its heptadiene chain. Curcuminoids keto-enol have one carbonyl (C=O) and one hydroxyl (-OH), which are located side by side and separated by methylene (=CH-) in its heptadiene chain^26,27.

 

 

Figure 2 Optimized structure of curcuminoids diketon, curcumin (A), demethoxycurcumin (B), bisdemethoxycurcumin (C).

 

Curcuminoids optimized structure is different for diketone (dk) and keto-eno (ke). Diketone optimized structure be in the non-planar form (Figure 2). This non-planar structure is caused by the two carbonyl groups (C=O), which are in cis position. This condition obtains high electron repulsion and has high energy refers to unstable. This instability is overcome by changing the position from cis to trans position until the structure becomes stable so that the structure becomes non-planar. Keto-enol optimized structure is planar. This planar structure is caused by hydrogen bonds formed between hydroxyl and carbonyl groups (Figure 3).

 

 

Figure 3 Optimized structure of curcuminoids keto-enol, curcumin (A), demethoxycurcumin (B), bisdemethoxycurcumin (C).

 

HOMO is the highest occupied molecular orbital, and LUMO is the lowest unoccupied molecular orbital. The study about molecular orbital means research about the reactivity of the molecule. The reactivity has a relation with ionization energy (I) and affinity of the compound (Table 1).

 

The display of HOMO-LUMO (Figure 4 and Figure 5) for each molecule can show molecular orbital distribution. Mostly, HOMO diketone spreads in the entire molecule. HOMO of demethoxhycurcumin is in one phenyl ring only. This is caused by the presence of one methoxy group, which shifts the HOMO area. HOMO of curcumin and bisdemethoxycurcumin spread evenly in its molecule. LUMO of diketone spread in the same area for curcumin, demethoxhycurcumin, and bisdemethoxycurcumin. HOMO of all keto-enol have same look, which spread evenly in its molecule. This happens for LUMO of keto-enol too.

 

Table 1: Chemical descriptors.

Molecule	HOMO (eV)	LUMO (eV)	I=-EHOMO (eV)	A=-ELUMO (eV)	Egap (eV)	η=(I-A)/2	μ= -(I+A)/2	ω= μ2/2η
Cdk	-5.660	-1.986	5.660	1.986	3.674	1.837	-3.823	3.979
DCdk	-5.633	-2.014	5.633	2.014	3.619	1.810	-3.823	4.039
BDCdk	-5.905	-2.014	5.905	2.014	3.891	1.946	-3.959	4.028
Cke	-5.279	-2.041	5.279	2.041	3.238	1.619	-3.660	4.137
DCke	-5.388	-2.068	5.388	2.068	3.320	1.660	-3.728	4.186
BDCke	-5.442	-2.068	5.442	2.068	3.374	1.687	-3.755	4.179

 

Figure 4 The display HOMO LUMO of curcuminoids diketone, curcumin (A), demethoxycurcumin (B), bisdemethoxycurcumin (C).

 

Figure 5: The display HOMO LUMO of curcuminoids keto-enol, curcumin (A), demethoxycurcumin (C), bisdemethoxycurcumin (D).

The charges for curcuminoids are different between diketone and keto-enol (Table 2). Most of the charges for carbon in the backbone structure of all curcuminoids show insignificant changes. Significant changes occur only in atoms directly linked to a functional group such as methoxy and hydroxy. Atomic charge in the molecule is essential to explain how a molecule can interact with another molecule to build intermolecular interaction. The atomic charge of the ligand causes the intermolecular interaction that may happen between ligand and enzyme. The atomic charges of curcuminoids are shown in Table 2.

 

The oxygen charge of curcuminoid diketone in heptadiene chains is more positive than curcuminoid keto-enol. The presence of methoxy in phenyl rings change the carbon bond that directly bonds to it (C3-O34 and C16-O36). Methoxy give an electron-withdrawing inductive effect. This happen too when hydroxyl bond to carbon in phenyl ring—the charge of carbon changes to be more positive.

 

The docking curcuminoid to Tribolium castaneum telomerase in molecular scale obtains two kinds of interactions molecular that happen between curcuminoid and amino acid residue in telomerase catalytic site. The binding energy from docking has been analyzed using Root Mean Square Distances (RMSD) values to standard inhibitors (BIBR1532). The RMSD values of the three curcuminoid compounds for two structures give values below 2 Å. The docking of curcuminoid compounds in Tribolium castaneum telomerase (GDP ID: 5CQG) has Binding energy and root mean square distance values shown in Table 3.

 

 

Table 2: Charge of curcuminoids.

	Phenyl ring 1						Heptadiene chains		Phenyl ring 2
	C3	O34	C38	C4	O35	C5	O20	O21	C16	O36	C39	C17	O37	C18
Cdk	0.354	-0.554	-0.218	0.314	-0.641	-0.172	-0.486	-0.485	0.354	-0.554	-0.218	0.314	-0.641	-0.172
DCdk	-0.194	-	-	0.359	-0.632	-0.161	-0.487	-0.479	0.354	-0.554	-0.218	0.314	-0.642	-0.172
BDCcd	-0.194	-	-	0.359	-0.633	-0.161	-0.481	-0.481	-0.194	-	-	0.359	-0.633	-0.161
Cke	0.354	-0.553	-0.215	0.312	-0.643	-0.172	-0.640	-0.604	0.354	-0.553	-0.216	0.312	-0.645	-0.171
DCke	-0.194	-	-	0.357	-0.635	-0.161	-0.640	-0.602	0.353	-0.215	-0.215	0.312	-0.643	-0.172
BDCke	-0.195	-	-	0.355	-0.635	-0.169	-0.640	-0.602	-0.196	-	-	0.356	-0.635	-0.159

 

 

Table 3. Docking output Curcuminoid to Tribolium castaneum telomerase.

Molecule/Ligand	Structure	Binding Energy (kkal/mol)	rmsd/ub (Å)	rmsd/lb (Å)
BIBR1532		-7,9	1.822	1.376
Cdk		-7,5	1.694	0.647
DCdk		-7,7	1.961	0.820
BDCdk		-7,6	1.611	1.120
Cke		-6,3	1.858	1.699
DCke		-6,0	1.946	1.197
BDCke		-6,2	1.984	1.366

 

Binding energy in Table 3 shows that curcuminoid in diketone and keto-enol structure can interact directly to catalytic active site telomerase. Binding energy curcuminoid diketone is lower (more stable) than curcuminoid keto-enol. The lower energy direct to more lone pair in oxygen. The more atoms have lone pairs in the ligand, the easier and more stable intermolecular interaction. The higher binding energy for curcuminoid keto-enol may cause by the hydrogen bonding formed between hydroxyl and carbonyl groups located side by side.

 

The binding energy of curcuminoid diketone decreases as the methoxy (-OCH3) is lost in one phenyl ring. The lowest binding energy is owned by demethoxycurcumin diketone. The loss of methoxy on one of the phenyl rings causes the smaller binding energy, making the interaction more stable. However, if both phenyl rings lose the methoxy, the energy will rise. It happens for bisdemethoxycurcumin diketone. The presence of methoxy in both phenyl rings can reduce the strength of oxygen (C=O) that interact in the heptadiene chain. The binding energy of curcumin is higher than the binding energy of bisdemethoxycurcumin for the diketone structure.

Therefore binding energy of curcuminoid keto-enol decreases as methoxy group (-OCH3) added. The presence of methoxy in both of phenyl ring is given more strength of oxygen (C=O and –OH) that interact in heptadiene chain. The lowest binding energy owned by curcumin keto-enol. The highest binding energy owned by demethoxycurcumin keto-enol. The binding energy of demethoxycurcumin is higher than binding energy of bisdemethoxycurcumin in keto-enol structure.

 

The docking output curcuminoid to Tribolium castaneum telomerase obtains some intermolecular interactions. Intermolecular interactions occur between functional groups in curcuminoid and residual amino acids of the telomerase enzyme's catalytic site. The bond distance obtained from the interaction between three curcuminoid compounds and the telomerase enzyme has a bond length below 5Å. The evaluation obtained for the docking three curcuminoid as ligands to Tribolium castaneum telomerase formed the interactions between curcuminoid with amino acid residues, bond types, and bond distances in Table 4.

 

 

 

 

Table 4. Interaction curcuminoid with amino acid in Tribolium castaneum telomerase.

Molecule/Ligand	Hydrogen Bond	Van der Waals Interaction
Curcumin Diketone (Cdk)	Arg 486 Met 482 Phe 495 Gly 495 Leu 554 Phe 494 Asn 493	Gly 553
Demethoxycurcumin Diketone (DCdk)	Arg 486 Met 482 Phe 494 Leu 554 Gly 553 Trp 498 Phe 494
Bisdemethoxycurcumin Diketone (BDCdk)	Arg 486 Met 482 Glu 549 Gly 553 Leu 554 Phe 394
Curcumin Keto-enol (Cke)	Ile 550 Leu 554 Asp 493 Asn 492 Phe 494 Arg 486 Leu 554 Lys 552 Gly 553 Glu 549
Demethoxycurcumin Keto-enol (DCke)	Ile 550 Glu 549 Gly 553 Arg 486 Gly 495 Trp 498	Glu 549 Met 482
Bisdemethoxycurcumin Keto-enol (BDCke)	Leu 554 Lys 552 Gly 553 Trp 498 Gly 495 Arg 557 Arg 486 Met 482	Glu 549

 

Intermolecular interactions occur between curcuminoids and telomerase enzymes are hydrogen bond and van der Waals interaction. Hydrogen bonds dominate the intermolecular interaction. Hydrogen bonds for the three curcuminoids diketone are obtained from C=O carbons with Arg486 and Met482. The hydrogen bond distance between C=O and Arg486 in curcumin, demethoxycurcumin, and bisdemethoxycurcumin is 2.4 Å, 2.3 Å, and 1.9 Å. The hydrogen bond distance decreases with the loss of the methoxy group on the phenyl ring, indicating the stronger interaction that occurs between carbonyl and the amino acid Arg486. The hydrogen bond occurs in the phenyl ring of the three curcuminoids diketone have different amino acid residues. The difference is due to the difference in the number of methoxy and hydroxy groups bound to the phenyl ring 1 and phenyl ring 2. The phenyl rings of curcumin diketone are surrounded by Phe495, Gly495, Leu554, Phe494, and Asn493. The phenyl rings demethoxycurcumin diketone is surrounded by Phe494, Leu554, Gly553, Leu554, and Trp498. The phenyl rings without methoxy groups, bisdemethoxycurcumin are surrounded by Glu549, Gly553, Leu554, and Phe394. Interaction van der Waals occurs only in curcumin’s phenyl ring, between the methoxy group (-OCH3) and Gly553.

 

Hydrogen bonds also dominate the interaction between the catalytic side of the telomerase enzyme and curcuminoid keto-enol. Hydrogen bond for the three curcuminoids keto-enol in the heptadiene chain relate to between C = O and hydroxy-OH carbonyl with different residues. Hydrogen bonding curcumin keto-enol occurs between C = O and -OH carbonyl with residues Ile550 and Leu554. Hydrogen bonds demethoxycurcumin keto-enol occur between C= O and -OH with Ile550, Glu549, and Gly553 while bisdemethoxycurcumin keto-enol occurs between C=O and -OH with Leu554, Lys552, and Gly553. Unlike the curcuminoid diketone, curcuminoids keto-enol have one van der Waals interaction in the pentadiene chain. The interaction van der Waals of the demetoxycurcumin and bisdemethoxycurcumin, which is between C=O and Gly549.

 

The hydrogen bond that occurs in the three curcuminoid diketone phenyl ring has different amino acid residues. The difference is the number of methoxy and hydroxy groups bound to phenyl ring left and phenyl ring. Phenyl ring of curcumin keto-enol is surrounded by Asp493, Asn492, Phe494, and Arg486. Phenyl ring of demethoxycurumin keto-enol surrounded by Arg486, Met482, Gly495, and Trp498. The ring without the methoxy group, bisdemethoxycurcumin, is surrounded by Trp498, Gly495, Arg557, Arg486, and Met482. The visualization shows that the more molecules bend, the easier the interaction will be. This condition also affects the value of binding energy for interactions between ligand and enzyme. Visualization of the interaction between Tribolium castaneum telomerase and six curcuminoids can be seen in Figure 6.

Figure 6: Tribolium castaneum telomerase interaction to curcumin diketone (Cdk) (a), demethoxycurcumin diketone (DCdk) (b), bisdemethoxycurcumin diketone (BDCdk) (c),  curcumin keto-enol (Cke) (d), demethoxycurcumin keto-enol (DCke) (e), bisdemethoxycurcumin keto-enol (BDCke) (f). 3D Visualization using PyMOL.

 

 

Figure 7: Tribolium castaneum telomerase curcumin diketone (yellow), demethoxycurcumin diketone (green), bisdemethoxycurcumin diketone (red). 3D Visualization using PyMOL.

 

 

Figure 8 Tribolium castaneum telomerase curcumin keto-enol (blue), demethoxycurcumin keto-enol (orange), bisdemethoxycurcumin diketone (magenta). 3D Visualization using PyMOL.

 

CONCLUSION:

Based on, DFT calculation for curcuminoid, the diketone optimized structure has a non-planar configuration, instead of curcuminoid keto-enol is planar. The docking output of these three curcuminoids to Tribolium castaneum telomerase obtained that curcuminoid diketone show better potency as an inhibitor, to inhibit telomerase enzyme. This condition because it has lower binding energy.

 

 

ACKNOWLEDGMENT:

The authors sincerely thank Mr. Yusuf Galenta who kindly helped this study.

 

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19.   Kharisma VD, Probojati RT, Murtadlo AAA, Ansori ANM, Antonius Y, Tamam MB. Revealing Potency of Bioactive Compounds as Inhibitor of Dengue Virus (DENV) NS2B/NS3 Protease from Sweet Potato (Ipomoea batatas L.) Leaves. Indian J Forensic Med Toxicol. 2020; 15(1): 1627–1632. DOI: 10.37506/ijfmt.v15i1.13644

20.   Kharisma VD, Agatha A, Ansori ANM, Widyananda MH, Rizky WC, Dings TGA, Derkho M, Lykasova I, Antonius Y, Rosadi I, Zainul R. Herbal combination from Moringa oleifera Lam. and Curcuma longa L. as SARS-CoV-2 antiviral via dual inhibitor pathway: A viroinformatics approach. J Pharm Pharmacogn Res. 2022; 10(1): 138-146.

21.   Ansori ANM, Susilo RJK, Fadholly A, Hayaza S, Nugraha AP, Husen SA. Antidiabetes type 2 phytomedicine: Mangosteen (Garcinia Mangostana l.)-A review. Biochem Cell Arch. 2020; 20: 3173-3177. DOI: 10.35124/bca.2020.20.S1.3173

22.   Khairullah AR, Solikhah TI, Ansori ANM, Fadholly A, Ramandinianto SC, Ansharieta R, Widodo A, Riwu KHP, Putri N, Proboningrat A, Kusala MKJ, Rendragraha BW, Putra ARS, Anshori A. A Review of an Important Medicinal Plant: Alpinia galanga (L.) Willd. Sys Rev Pharm. 2020; 11(10): 387-395. DOI: 10.31838/srp.2020.10.62

23.   Kharisma VD, Widyananda MH, Ansori ANM, Nege AS, Naw SW, Nugraha AP Tea catechin as antiviral agent via apoptosis agonist and triple inhibitor mechanism against HIV-1 infection: A bioinformatics approach. J Pharm Pharmacogn Res. 9(4): 435-445.

24.   Kharisma VD, Ansori ANM, Widyananda MH, Utami SL, Nugraha AP. Molecular simulation: The potency of conserved region on E6 HPV-16 as a binding target of black tea compounds against cervical cancer. Biochem Cell Arch. 2020; 20: 2795-2802. DOI: 10.35124/bca.2020.20.S1.2795

25.   Widyananda MH, Pratama SK, Samoedra RS, Sari FN, Kharisma VD, Ansori ANM, Antonius Y (2021) Molecular docking study of sea urchin (Arbacia lixula) peptides as multi-target inhibitor for non-small cell lung cancer (NSCLC) associated proteins. J Pharm Pharmacogn Res 9(4): 484–496.

26.   Ansori ANM, Fadholly A, Proboningrat A, Antonius Y, Hayaza S, Susilo RJ, Inayatillah B, Sibero MT, Naw SW, Posa GAV, Sucipto TH, Soegijanto S. Novel Antiviral Investigation of Annona squamosa Leaf Extract against the Dengue Virus Type-2: In vitro Study. Phcog J. 2021; 13(2): 456-462. DOI: 10.5530/pj.2021.13.58

27.   Ansori AN, Kharisma VD, Parikesit AA, Dian FA, Probojati RT, Rebezov M, Scherbakov P, Burkov P, Zhdanova G, Mikhalev A, Antonius Y, Pratama MRF, Sumantri NI, Sucipto TH, Zainul R. Bioactive Compounds from Mangosteen (Garcinia mangostana L.) as an Antiviral Agent via Dual Inhibitor Mechanism against SARS-CoV- 2: An In Silico Approach. Phcog J. 2022; 14(1): 85-90. DOI: 10.5530/pj.2022.14.12

 

 

 

Accepted on 29.04.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(10):4817-4824.