Orthosiphon aristatus (O. aristatus) is a herbal plant that has antioxidant activity. This study was conducted in a preliminary study of the potential active compound O. aristatus with in silico software pyrex autodock vina method, and visualization using biovia discovery studio. Results from the study in silico showed that O.aristatus extract has potential as an antioxidant compound. Result value of binding affinity with SOD receptor proteins having more negative values compared to control compounds. The interaction of O.aristatus extract is quite potential as an antioxidant, through hydrogen bonding that is equal to control, namely vitamin EOrthosiphon aristatus (O. aristatus) adalah tanaman herbal yang memiliki aktivitas antioksidan. Penelitian ini merupakan studi awal tentang senyawa aktif potensial O. aristatus dengan metode in silico pyrex autodock vina, dan visualisasi menggunakan biovia discovery studio. Hasil dari penelitian di silico menunjukkan bahwa ekstrak O.aristatus memiliki potensi sebagai senyawa antioksidan. Nilai hasil afinitas pengikatan dengan protein reseptor SOD memiliki nilai yang lebih negatif dibandingkan dengan senyawa kontrol. Interaksi ekstrak O.aristatus cukup potensial sebagai antioksidan, melalui ikatan hidrogen yang sama dengan kontrol, yaitu vitamin E

Faizal, Imam Agus

Novita, Dian

English

Medical Laboratory Analysis and Sciences Journal (Melysa)

  Journal homepage: melysajournal.com *Corresponding author: imamdfaizal@stikesalirsyadclp.ac.id   In Silico Studi Orthosiphon aristatus as Antioxidant   Dian Novita Wulandari1a, Imam Agus Faizal2b* 1  Department of Pharmacy University of Islam Malang, Malang, East Java, Indonesia 2 Department of Applied Bachelor's Degree of Medical Laboratory Technology, Al-Irsyad University of  Cilacap, Cilacap, Central Java, Indonesia. a diannovi@unisma.ac.id b  imamdfaizal@stikesalirsyadclp.ac.id* * corresponding author   ARTICLE INFO ABSTRACT Article history: Received date: 2020 September 27th Revised date: 2020 October 20th Accepted: 2020 October 23rd Published: 2020 November 7th Orthosiphon aristatus (O. aristatus) is a herbal plant that has antioxidant activity. This study was conducted in a preliminary study of the potential active compound O. aristatus with in silico software pyrex autodock vina method, and visualization using biovia discovery studio. Results from the study in silico showed that O.aristatus extract has potential as an antioxidant compound. Result value of binding affinity with SOD receptor proteins having more negative values compared to control compounds. The interaction of O.aristatus extract is quite potential as an antioxidant, through hydrogen bonding that is equal to control, namely vitamin E. Keywords: Orthosiphon aristatus  In Silico Antioxidant Superoxide dimutate   Copyright (c) 2020 The Author This is an open access article under the CC-BY-SA license   INTRODUCTION Free radicals play an important role in aerobic metabolism. Antioxdants Reactive oxygen species (ROS) and other free radicals are responsible for many diseases, such as arteriosclerosis, heart disease, aging, and cancer. Antioxidant agents act as free radicals or reactive oxygen species (ROS) scavengers by stopping radical chain reactions. ROS can trigger lipid peroxidation as a precursor to oxidation process. In the body, there is an intracellular ROS system scavengers to inhibit further oxidation processes; and this includes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and others.1 Free radicals such as ROS, including hydroxyl radicals, superoxide anions, and hydrogen peroxide, play an important role in increasing the destruction of living tissues. The antioxidant activity of phenolic compounds is found mainly because it inhibits its redox through neutralization and free radical cooling.2 Aerobic organisms normally constantly produce reactive oxygen species (ROS) as a by-product of aerobic metabolism that can play a role in various natural processes in the body. These oxygen derivates under normal circumstances will be neutralized by the enzyme's antioxidant defense system (superoxide dismutase, catalase, glutathione peroxidase) and non-enzyme antioxidants (vitamin C, vitamin E, gluglutation).3 O. aristatus is a herbal plant from the Lamiaceae family that is easy to find in Southeast Asian countries such as the Philippines, Malaysia, Brunei, Thailand and Indonesia. The leaves are extensively processed to treat several dangerous diseases such as gonorrhea, diabetes, or kidney stone. About 116 compounds were isolated from O. aristatus and classified as essential oil, favonoid, or phenolic acid.4 O. aristatus main constituents are sinensetin, eupatorine, and rosmarinic Vol. 2 Issue 2, November 2020, page 66-71 ISSN: 2657-1471 (Online) ISSN: 2656-937X (Print) DOI: 1035584/melysa.v2i2.59      Journal homepage: melysajournal.com *Corresponding author: imamdfaizal@stikesalirsyadclp.ac.id  Wulandari, et al., 2020  67 acid which has a lot of pharmacological activity.5 In addition to O. aristatus also contains isosinensetin, orthosiphol A-E, glycosides, kadein, phytosterols, predensin, paclitaxel, tannin, essential oils.6 O. aristatus has a phytochemical composition with various pharmacological activities that can improve the level of human health. O. aristatus extract can also be a potential diabetic wound healing phytomedicin for further preclinical and clinical studies 7. Flavonoid compounds can prevent free radicals and stabilize ROS by bonding with the free electrons of ROS and neutralize species oxygen to a stable form that can delay, prevent, or eliminate oxidative damage to target molecules, for example: proteins, lipids, and DNA due to free radicals.8 In this preliminary study, researchers wanted to find out how much potential O. aristatus extracts have by using the in silico. In silico method began to be ogled because of the advantages of being cheap and the results are faster. In silico is a research method that utilizes computing and database technology to develop further research.9 The receptor used is superoxide dismutase (SOD). The parameter used is binding affinity to determine the bonding power of exogenous antioxidant compounds with their receptors. Hydrogen bonds are also used in addition to bond strength through interaction with amino acid residues of receptor proteins through hydrogen bonding.10  MATERIALS AND METHODS Research design is descriptive-analytical research. Identification of active compounds from O. aristatus extracts was obtained from previous research. The active compounds used are sinensetin, isosinensetin, orthosiphol A, orthosiphol B.11 The active compounds of O.aristatus extract were obtained from previous research. The 3D structure of the active ingredient compound and control is downloaded from the Pub Chem (https://pubchem.ncbi.nlm.nih.gov) server.12 The 3D structure of each is downloaded in sdf format, SOD receptor protein from human downloaded from (http://www.uniprot.org/).13 The protein sequence obtained and modeling in https://swissmodel.expasy.org/.14 The obtained protein is then downloaded and stored in pdb format. The docking process is carried out using a pyrx (autodock vina) program. The docking results are then visualized. To see the interaction between receptors and ligands use the Biovia Discovery Studio program.15 Affinity binding results are selected from the most negative values. Negative values indicate ligand conformation with the most stable receptors. The conclusion drawn is seen from the most minus affinity binding values because the smaller the affinity binding value, the binding ability between the ligand used and the stronger the receptor.16  RESULTS AND DISCUSSION Potential Analysis of O. aristatus   Extract as an antioxidant compound by in silico method. The study in silico as a preliminary test predicts the potential of active compounds of O. aristatus  by linking ligands which are the active compounds of O.aristatus with its receptor protein SOD. The docking results are shown as in table 1.  Table 1. Analysis of the potential of antioxidant active compounds from O. aristatus extracts against its receptor proteins by in silico method Ligan ID CID Receptor Binding affinity (kcal/mol) Ascorbic acid* 54670067 SOD -5,2 Tocopherol* 86472 SOD -3,6 Sinensetin  145659 SOD -4,6 Isosinensetin 632135 SOD -4,7 Orthosiphol A 15385858 SOD -4.0 Orthosiphol B 15385859 SOD -5,7 *control      Journal homepage: melysajournal.com *Corresponding author: imamdfaizal@stikesalirsyadclp.ac.id  Wulandari, et al., 2020  68  From table 1 it is seen that the affinity binding values of O.aristatus extract have more negative values compared to tocopherol and ascorbic acid. In general, O.aristatus extract has a binding affinity value that is more negative and equal to its control. Result O.aristatus extract is quite potent as a source of antioxidants.  Analysis of Ligand Interactions of Active Compounds Extracted from O. aristatus with Superoxide dismutase as Receptor Proteins Analysis of the potential of O.aristatus extracts active compounds namely sinensetin, isosinensetin, orthosiphol A, orthosiphol B shows the potential as antioxidant compounds seen from binding affinity values that are more negative and the same compared to the control. In addition to the analysis of its potential judging by the binding affinity value, it also looked at the interaction of ligands with amino acid residues from receptor proteins in silico. Analysis of interactions is done to find out the bond strength between these active compounds. Active compounds that are predicted to have strong bonds with target proteins are active compounds that have hydrogen bonds with amino acid residues of receptor proteins that are the same as the controls. Analysis of ligand interactions with active compounds is shown in table 2.  Table 2. Analysis of ligand interactions of active compounds extracting O. aristatus with Superoxide dismutase receptor proteins Ligand ID Receptor Interaction Ascorbid acid* SOD Hydrogen bond : Asp 110, Ser 106, Ser 108, Ile 105  Van der Waals bond: Ser 103, Val 104, Asn 27, Gln 23, Gly 28, Ser 26, Gly 109, Cys 112 Tocopherol* SOD Hydrogen bond : A 3 Van der Waals bond : Ala 153, Ala 2, Gln 154, Met 1, Phe 51, Glu 50, Lys 4, Glu 22, Lys 24 Sinensetin  SOD Hydrogen bond : Phe 21, Ala 5 Van der Waals bond : Val 8, Ala 56, Gly 57, Gly 52, Gly 62, Ile 152 Isosinensetin SOD Hydrogen bond : Ser 60 Van der Waals bond : Lys 4, Gln 154, Asn 54 Orthosiphol A SOD Hydrogen bond: Ile 152, Phe 51, Ala 153, Ala 2, Glu 50, Glu 22, Lys 24 Van der Waals bond : Lys 4 Orthosiphol B SOD Hydrogen bond : Ser 69, His 81, Asn 66 Van der Waals bond :Pro 63, Arg 70, Lys 71, Thr 136, Glu 133 Bold and underline indicate the existence of a complex (SOD-ligand) has the same interaction with its control * control       Journal homepage: melysajournal.com *Corresponding author: imamdfaizal@stikesalirsyadclp.ac.id      Figure 1. 2D Visualisasion of Sinensetin linking SOD  Figure 2. 2D Visualisasion of Isosinensetin linking SOD   Figure 3. 2D Visualisasion of Orthosiphol A linking SOD   Figure 3. 2D Visualisasion of Orthosiphol B linking SOD  Recently, the molecular basis of the anti-inflammatory action of a flavonoid-rich chloroform extract fraction of O. aristatus leaves and its key bioactive compounds, eupatorin and sinensetin, has been elucidated. Eupatorin and sinensetin alleviated carrageenan-induced in flamation in mice. Furthermore, the two flavonoids attenuated the production of nitric oxide (NO), prostaglandins, and tumour necrosis factor a (TNF-oc) in lipopolysaccharide-activated J774 murine macrophage cells. TNF-oc is a key regulator of inflammatory response and plays a central role in the pathogenesis of inflammatory disorders. The findings thus support the hypothesis that inhibition of the release or production;of inflalftmatory mediators from activated inflammatory cells underlies the anti-inflammatory properties of eupatorin and sinensetin.17 flavonoids can protect our body of the subsequent reactions of ROS and RNS by capturing ROS, blocking reactions propagation and stimulate the formation of endogenous antioxidants such as GPx, SOD and Catalase and reduce MDA levels due to the absence of lipid peroxidation (PUFA) and reduce 8-OHdG levels because HO* which normally enters the DNA reacts already captured by flavonoids. In addition, flavonoids can function as anti-inflammatory because flavonoids can inhibit formation of pro inflammatory cytokines such as TNF-α, IL-6, IL-1β and interferon-γ.18      Journal homepage: melysajournal.com *Corresponding author: imamdfaizal@stikesalirsyadclp.ac.id  Wulandari, et al., 2020  70 Antioxidant and Anti-inflammatory activity, four proteins structure has been selected for target identification and validation. Three targets for evaluation of antioxidant activity was selected based on pathways involving active participation. Research shows that many phytochemicals act as agonists and increase the activity of Superoxide dismutase (SOD), Glutathione peroxidase (GPX) and Catalase (CAT). SOD, GPx and CAT agonists can increase their activity and thus can overcome stress-related ROS induction. Therefore, these three proteins SOD, GPx and CAT) have been selected as targets of phytochemical antioxidant activity.1 Sinensetin is a polymethoxylate flavonoid that has strong anticancer activity and various other pharmacological benefits and has promising potential in terms of its intended toxicity activity. In this review, insights into the pharmacological activity of sinensetin and its mechanism of action serve as a useful resource for a more thorough and comprehensive understanding of sinensetin as a potential prime candidate for drug discovery.16 O. aristatus contain a secondary metabolite sinensetin which belongs to the group of flavonoid compounds. Sinensetin has potential as an antiviral agent and immunomodulator.19 in addition, the content of O. aristatus also contains tocopherol molecules that function as antioxidants. Recently, the tocopherol cyclase enzyme has been identified as a key enzyme for tocopherol biosynthesis which plays a key role in antioxidants against free radicals.20  CONCLUSIONS Based on preliminary tests in silico extract O. aristatus compound has potential as an antioxidant. It proved by affinity binding values with amino acid residues from SOD have more negative compared to controls. From the interaction data, O. aristatus extract is quite potent as an antioxidant, through hydrogen bonding with amino acid residues: Phe 51, Ala 153, Ala 2, Glu 50, Glu 22, Lys 24 with SOD.  REFERENCES 1.  Rana S, Dixit S, Mittal A. In silico target identification and validation for antioxidant and anti-inflammatory activity of selective phytochemicals. Brazilian Arch Biol Technol. 2019;62:1-11. doi:10.1590/1678-4324-2019190048 2.  Silalahi M. Orthosiphon stamineus Benth (Uses and Bioactivities). Indones J Sci Educ. 2019;3(1):26. doi:10.31002/ijose.v3i1.729 3.  Lilyawati SA, Fitriani N, Prasetya F. 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In silico studi of Orthosiphon aristatus as antioxidant

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In silico studi of Orthosiphon aristatus as antioxidant

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Medical Laboratory Analysis and Sciences Journal (Melysa)