Screening of Compounds in Temu Ireng (Curcuma aeruginosa Roxb.) as Tuberculosis drug using Bioinformatics Design

 

Sri Wahyuningsih¹, Alyaa F. Dibha², Viol D. Kharisma³, Affan A. Murtadlo³, A. N. M. Ansori⁴, Muhammad H. Widyananda^3,5, Maksim Rebezov^6,7,8, Pavel Burkov⁹, Marina Derkho⁹, Pavel Scherbakov⁹, Nikolai Maksimiuk¹⁰, Alevtin Miftakhutdinov⁹, Rahadian Zainul^11,12*

¹Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia.

²Department of Chemistry, Faculty of Mathematics and Natural Sciences,

Brawijaya University, Malang, Indonesia.

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

⁴Professor Nidom Foundation, Surabaya, Indonesia.

⁵Department of Biology, Faculty of Mathematic and Natural Sciences, Universitas Brawijaya, Malang, Indonesia

⁶Department of Scientific Research, Russian State Agrarian University - Moscow

Timiryazev Agricultural Academy, Moscow, Russian Federation.

⁷Faculty of Biotechnology and Food Engineering, Ural State Agrarian University,

Yekaterinburg, Russian Federation.

⁸Department of Scientific Research, K.G. Razumovsky Moscow State University of Technologies and Management (The First Cossack University), Moscow, Russian Federation.

⁹Institute of Veterinary Medicine, South Ural State Agrarian University, Troitsk, Russian Federation.

¹⁰Institute of Medical Education, Yaroslav-the-Wise Novgorod State University,

Velikiy Novgorod, Russian Federation.

¹¹Department of Chemistry, Faculty of Mathematics and Natural Sciences,

Universitas Negeri Padang, Padang, Indonesia.

¹²Center for Advanced Material Processing, Artificial Intelligence, and Biophysic Informatics (CAMP-BIOTICS), Universitas Negeri Padang, Padang, Indonesia.

 

ABSTRACT:

Temu ireng (C. aeruginosa Roxb.) is a rhizome plant that is well known among Indonesians as a type of herbal plant due to the presence of bioactive compounds with numerous benefits. One of them is to act as an anti-bacterial agent. Tuberculosis is a symptomatic chronic condition triggered by a bacterial infection of the lungs in humans. The goal of this study was to use a bioinformatic technique to identify probable substances from C. aeruginosa Roxb. as a TB drug. C. aeruginosa Roxb. compounds' pharmacokinetics and druglikeness function Antibacterial activity was calculated using SwissADME analysis, antibacterial activity using QSAR analysis, and interaction between compounds and the protein crystal structure of M. tuberculosis using molecular docking interpretation. The 1.8-cineole compound's analytical results reached Lipinski's rule of five and demonstrated great ADMET modeling as a future drug nominee. This is supported by QSAR analysis, which demonstrates that 1.8-cineole can act as an antituberculosic. Besides this, the docking binding energy of 1.8-cineole was -4.20 kcal/mol following the molecular identification, suggesting that the bonds formed were quite constant.

 

 

 

 

INTRODUCTION: 

Plants are a class of living thing with a number of advantages for humans because they contain bioactive molecules that can be consumed as an alternative therapy^1,2,3,4,5. Zingiberaceae is a plant group that has gotten a lot of attention and investigation in the area of pharmaceutical research^6,7,8. This plant group has been shown to be antifugal, cytotoxic and anticancer, antioxidant, insecticidal, anti-inflammatory, anti-virus, and anti-bacterial^9,10. Temu Ireng (C. aeruginosa Roxb.) is a member of the Genus that is well-known among Indonesians as a source of ethnomedicine (Jamu)^11,12,13. This plant is a rhizome that appears to contain bioactive molecules, one of which acts as an anti-bacterial such as camphor, 1.8-cineole, curdione, germacrone, and curzerenone (Figure 1)^14,15,16. Several studies have found that C. aeruginosa Roxb. Is capable of suppressing or killing Escherichia coli bacteria, Pseudomonas aeruginosa, Bacillus cereus, and Staphylococcus aureus^17,18,19.

 

Tuberculosis is a form of infection triggered by the bacterium Mycobacterium tuberculosis which then targets the circulatory tract and belongs to the category of diseases that causes the death of patients with chronic globally due to resistance to existing treatments^20,21,22. When an individual becomes infected with this disease, they will undergo breathing problems, fever, night sweats, and weight loss, which will worsen if the air in their surroundings is poor^23,24,25. Several medical professionals are working on developing moderate treatments for this disease, varying from systemic treatment to the use of secondary metabolites of living things^26,27,28. Indeed the Indonesians suspect Temu ireng (C. aeruginosa Roxb.) can be used as a TB therapeutic agent. To illustrate this, proof research must be conducted, one of which implements the bioinformatical design (molecular docking). This technique includes a computerized system to monitor the interaction between specific compounds and the intentional target^29,30. The focus of this research is to define one or many potential secondary metabolites in C. aeruginosa Roxb. that seem to be anti-tuberculosis.

 

 

Figure 1: A. camphor, B. 1.8-cineole, C. curdione, D. germacrone, and E. curzerenone

METHOD:

Preparation of Ligands:

The chemical compounds that used in this study are camphor, 1.8-cineole, curdione which are the major components of Temu Ireng (C. aeruginosa Roxb.) from Indonesia [7]. Also, germacrone and curzerenone which the main compounds in C. aeruginosa Roxb. From Thailand [6]. The three-dimensional of camphor (CID: 2537), 1.8-cineole (CID: 2758), curdione (CID: 6441391), germacrone (CID: 6436348), and curzerenone (CID: 3081930) were downloaded from the PubChem database website (http://pubchem.ncbi.nlm.nih.gov) with PDB format. As an evalution, rifampicin (CID: 135398735) is a drug for tuberculosis drug and used as a control positive in this research^31,32,33.

 

Preparation of Protein:

The M. tuberculosis crystal structure which is complexed with Rifampicin was obtained from the Protein Data Bank website, the crystal structure was downloaded and saved in SDF format with PDB ID: 5UHB (https://www.rcsb.org/structure/5UHB). Afterward, the ligand and water that attached in protein will be removed and re-saved in PDB format with Discovery Studio software. Subsequently, the energy of crystal structure of M. tuberculosis minimized with PyRx Virtual Screening Tool software^34,35,36.

 

Pharmacokinetics and Druglikeness Characteristic of The Compounds from C. aeruginosa Roxb.

The absorption, distribution, metabolism, and excretion of the compounds were evaluated using the website tools (http://www.swissadme.ch), the chemical structure is drawn, or a list of SMILES of the major compounds of chemical of C. aeruginosa Roxb. structure is written. Subsequently, the run button pressed and the website will determine the parameters^37,38,39.

 

QSAR Evaluation with PASS server:

The drug-like ligand was tested for QSAR analysis using the PASS server website (http://way2drug.com/passonline/predict.php). The drug candidates were analyzed using Quantitative Structure-Activity Relationship (QSAR) to investigate the antibacterial activity of the compounds^40,41,42.

 

Drug Screening Molecule with Insilico Method:

The drug screening molecule of the major components of C. aeruginosa Roxb. from Indonesia and Thailand which were camphor, 1.8-cineole, curdione, germacrone and curzerenone. The method was carried out on the PyRx application using the Autodock Vina 1.1.2 menu. This method used to calculate the energy minimum of molecules that interacted with Mycobacterium tuberculosis crystal protein structure. On the other hand, Rifampin (RFP) was being docked with the Mycobacterium tuberculosis protein to the same binding area, to evaluate the binding affinity differences of the major compounds and the synthetic drug of tuberculosa disease. Ligand and protein interaction in 2D and 3D was evaluated by using Discovery Studio software^43,44,45,46.

 

RESULTAND DISCUSSION:

Preparation of Ligand and Protein:

Camphor, 1.8-cineole, curdione, germacrone and curzerenone are the main components in temu ireng (C. aeruginosa Roxb.) in Indonesia and Thailand. The three-dimensional structure of these compounds was obtained from PubChem website^47,48. The compounds were then opened in Discovery Studio to examine the 3D structure and saved in PDB format^49,50. The compounds were docked with M.  tuberculosis crystal structure (5UHB), this crystal structure was acquired from protein data bank, the water and native ligand from this protein were removed and saved in PDB extension. The components of C. aeruginosa Roxb. docked list with M. tuberculosis crystal structure (5UHB) was defined in Table 1.

 

Pharmacokinetics and Druglikeness Characteristics Result of The Compound:

The ADME and druglikeness of the compounds from Curcuma aeruginosa Roxb. were explained with the Swiss ADME tools. From this website, the lipophilicity, water solubility, gastrointestine absorption, blood brain barrier, and skin permeation obtained. Table 2 was the pharmacokinetics and druglikeness characteristic result of each compound.

 

Table 1: The components of Curcuma aeruginosa Roxb. with Mycobacterium tuberculosis crystal structure (5UHB)

Compound in Curcuma aeruginosa Roxb.	Protein
Camphor	5UHB
1.8-cineole	5UHB
Curdione	5UHB
Germacrone	5UHB
Curzerenone	5UHB
Rifampin	5UHB

 

QSAR Analysis of The Compounds in C. aeruginosa Roxb. with PASS online and Toxicity Level:

QSAR analysis of camphor, 1,8-cineol, curdione, germacrone, and curzerenone was performed using the online PASS website server. Camphor, curdione, germacrene, curzerenone have antibacterial and antibiotic activity shown in Table 4. However, 1,8-cineole has antituberculosis activity and has the same activity as rifampin as a drug for tuberculosis. Rifampin has an activity with Mycobacterium tuberculosis crystal structure and it proved by research that shown in Ferrari and Patrizio 2021^51,52,53.

 

Table 2. Pharmacokinetics and Druglikeness Characteristics of the compounds

Compound Name	Water solubility (mol/L)	Pharmacokinetics			Druglikeness (Lipinski Rule)
		GI absorption	Blood Brain Barrier	Skin Permeation (Log Kp / cms-1)
Camphor	2.52 e-3, soluble	High	Yes	-5.67	Yes, 0 violation
1.8-cineole	3.53 e-3, soluble	High	Yes	-5.30	Yes, 0 violation
Curdione	9.59 e-4, soluble	High	Yes	-5.86	Yes, 0 violation
Germacrone	2.29 e-4, soluble	High	Yes	-5.18	Yes, 0 violation
Curzerenone	3.73 e-5, moderately soluble	High	Yes	-4.84	Yes, 0 violation
Rifampin	1.83 e-5, moderately soluble	Low	No	-7.44	No, 3 violations

 

Table 3: Physicochemichal characteristics of the compounds

Compound Name	Formula	Molecular Weight (g/mol)	Number of H-bond acceptor	Number of H-bond donor	Molar Refractivity
Camphor	C10H16O	152.23	1	0	45.64
1.8-cineole	C10H18O	154.25	1	0	47.12
Curdione	C15H24O2	236.35	2	0	72.03
Germacrone	C15H22O	218.33	1	0	70.88
Curzerenone	C15H18O2	230.30	2	0	69.16
Rifampin	C43H58N4O12	822.94	14	6	234.22

 

Table 4: QSAR Analysis of The Compounds with PASS server

 

 

 

Drug Screening Molecule with Insilico Method Results:

In this research, the molecular docking analysis was done by using PyRx and the molecular docking analysis was led to get the binding energy and RMSD value. The compounds in C. aeruginosa Roxb were used as a ligand, rifampin as a drug that used for TBC disease, and Mycobacterium tuberculosis crystal structure protein used as a protein. The OpenBabel menu was used to minimize the energy of the compounds and the molecule in C. aeruginosa Roxb were added to the Vina Wizard menu. The grid box of the molecular docking analysis was set with X= -26.284, Y= 12.5976, Z= 58.9679 and the dimension with X = 25.000 Å, Y = 25.000 Å, and Z= 25.000 Å. Table 5 described the molecular docking analysis result of the compounds in C. aeruginosa Roxb. From Table 5 the binding energy of curdione has the lowest score from the other compounds in C. aeruginosa Roxb. On the other hand, the rifampin still has the higher score than the curdione. The RMSD value can be used to guess the interaction between ligand and protein^54,55. Theoretically, a decreased binding energy can make the protein and ligand complex more stable and enable the ligand to better fit the protein target^56,57. Rifampin was used as a control positive in molecular docking analysis. It is due to rifampin used as a first-line antituberculosis medication, targets RNA polymerase (RNAP)^58,59,60.

 

Table 5: Molecular Docking Analysis of The Compounds in C. aeruginosa Roxb with the Mycobacterium tuberculosis crystal structure protein (5UHB).

No	Compound	Protein	Binding Energy (kcal/mol)	RMSD (Å)	Hydrogen Bond	Amino Acid
1	Camphor	5UHB	-4.00	0	2	Arg C:163, Asn C:443
2	1.8-cineole		-4.20	0	1	Arg C:454
3	Curdione		-5.30	0	2	Gln C:614, Arg C:613
4	Germacrone		-5.00	0	1	Val C:894
5	Curzerenone		-5.00	0	1	Arg C:677
6	Rifampin		-6.00	0	2	His C:1035, Arg C:613

 

 

Figure 2: 2D and 3D structure of molecular docking between camphor and 5UHB

 

 

Figure 3: 2D and 3D structure of molecular docking between 1.8-cineole and 5UHB

 

 

Figure 4: 2D and 3D structure of molecular docking between curdione and 5UHB

 

Figure 5: 2D and 3D structure of molecular docking between germacrone and 5UHB

 

 

Figure 6: 2D and 3D structure of molecular docking between curzerenone and 5UHB

 

 

Figure 7: 2D and 3D structure of molecular docking between rifampin and 5UHB

 

CONCLUSION:

Tuberculosis is a disorder that targets the lungs, potentially cause the sufferer to suffer from a consistent cough that is soaked in blood at times. Further to that, this is an important pathogen that is destructive if not properly treated. Bioinformatic investigations aid in the accelerated exploration of antituberculosis agents. The molecular docking method was used in this study to find, create, and propose a new antituberculosis compound for oral administration. After comparing the Pharmacokinetics and Druglikeness, QSAR, and molecular docking of five compounds found in C. aeruginosa Rox. (champor, 1.8 cineole, curdione, Germacrone, and Curzerenone) to the crystal structure of M. tuberculosis (5UHB), it was discovered that 1.8 cineole had significant antituberculosis potential.

 

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45.    Husen SA, Syadzha MF, Setyawan MF, Pudjiastuti P, Ansori ANM, Susilo RJK et al. Evaluation of the combination of sargassum duplicatum, sargassum ilicifolium, abelmoschus esculentus, and garcinia mangostana extracts for open wound healing in diabetic mice. Systematic Reviews in Pharmacy. 2020; 11(9): 888-892. DOI: 10.31838/srp.2020.9.129

46.    Wijaya RM, Hafidzhah MA, Kharisma VD, Ansori ANM, Parikesit AP. COVID-19 In Silico Drug with Zingiber officinale Natural Product Compound Library Targeting the Mpro Protein. Makara J Sci. 2021; 25(3): 5. DOI: 10.7454/mss.v25i3.1244

47.    Ansori ANM, Fadholly A, Kharisma VD, Nugraha AP. Therapeutic potential of avian paramyxovirus serotype 1 for cancer therapy. Biochemical and Cellular Archives. 2020;20:2827-2832. DOI: 10.35124/bca.2020.20.S1.2827

48.    Prahasanti C, Nugraha AP, Kharisma VD, Ansori ANM, Ridwan RD, Putri TPS et al. Un enfoque bioinformático de la exploración con compuestos de hidroxiapatita y polimetilmetacrilato como biomaterial de implantes dentales. Journal of Pharmacy and Pharmacognosy Research. 2021; 9(5): 746-754.

49.    Kharisma VD, Ansori ANM, Fadholly A, Sucipto TH. Molecular mechanism of caffeine-aspirin interaction in kopi balur 1 as anti-inflammatory agent: A computational study. Indian Journal of Forensic Medicine and Toxicology. 2020; 14(4): 4040-4046. DOI: 10.37506/ijfmt.v14i4.12274

50.    Kharisma VD, Widodo N, Ansori ANM, Nugraha AP. A vaccine candidate of zika virus (ZIKV) from polyvalent conserved b-cell epitope on viral glycoprotein: In silico approach. Biochemical and Cellular Archives. 2020;20:2785-2793. DOI: 10.35124/bca.2020.20.S1.2785

51.    Ansori ANM, Kharisma VD, Nugraha AP. Phylogenetic and pathotypic characterization of avian paramyxovirus serotype 1 (APMV-1) in Indonesia. Biochemical and Cellular Archives. 2020;20:3023-3027. https://doi.org/10.35124/bca.2020.20.S1.3023

52.    Padmi H, Kharisma VD, Ansori ANM, Sibero MT, Widyananda MH, Ullah E, Gumenyuk O, Chylichcova S, Bratishko N, Prasedya ES, Sucipto TH, Zainul R. Macroalgae Bioactive Compounds for the Potential Antiviral of SARS-CoV-2: An In Silico Study. Journal of Pure and Applied Microbiology. 2022; 16(2): 1018-1027. DOI: 10.22207/JPAM.16.2.26

53.    Antonius Y, Kharisma VD, Widyananda MH, Ansori ANM, Trinugroho JP, Ullah ME, Naw SW, Jakhmola V, Wahjudi M. Prediction of Aflatoxin-B1 (AFB1) Molecular Mechanism Network and Interaction to Oncoproteins Growth Factor in Hepatocellular Carcinoma. J Pure Appl Microbiol. 2022;16(3):1844-1854. doi: 10.22207/JPAM.16.3.29

54.    Dibha AF, Wahyuningsih S, Ansori ANM, Kharisma VD, Widyananda MH, Parikesit AA, Sibero MT, Probojati RT, Murtadlo AAA, Trinugroho JP, Sucipto TH, Turista DDR, Rosadi I, Ullah ME, Jakhmola V, Zainul R. Utilization of Secondary Metabolites in Algae Kappaphycus alvarezii as a Breast Cancer Drug with a Computational Method. Pharmacognosy Journal. 2022; 14(3): 536-543. DOI: 10.5530/pj.2022.14.68

55.    Aini NS, Ansori ANM, Kharisma VD, Syadzha MF, Widyananda MH, Murtadlo AA, et al. Potential Roles of Purslane (Portulaca oleracea L.) as Antimetabolic Syndrome: A Review. Pharmacognosy Journal. 2022; 14(3): 710-714. DOI: 10.5530/pj.2022.14.90

56.    Listiyani P, Kharisma VD, Ansori AN, Widyananda MH, Probojati RT, Murtadlo AA, et al. In Silico Phytochemical Compounds Screening of Allium sativum Targeting the Mpro of SARS-CoV-2. Pharmacognosy Journal. 2022; 14(3): 604-609. DOI: 10.5530/pj.2022.14.78

57.    Aini NS, Kharisma VD, Widyananda MH, Murtadlo AA, Probojati RT, Turista DD, et al. In Silico Screening of Bioactive Compounds from Syzygium cumini L. and Moringa oleifera L. Against SARS-CoV-2 via Tetra Inhibitors. Pharmacognosy Journal. 2022;14(4):267-272. DOI: 10.5530/pj.2022.14.95

58.    Aini NS, Kharisma VD, Widyananda MH, Murtadlo AA, Probojati RT, Turista DD, et al. Bioactive Compounds from Purslane (Portulaca oleracea L.) and Star Anise (Illicium verum Hook) as SARS-CoV-2 Antiviral Agent via Dual Inhibitor Mechanism: In Silico Approach. Pharmacognosy Journal. 2022;14(4):352-357. DOI: 10.5530/pj.2022.14.106

59.    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

60.    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 23.03.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(10):4875-4880.