IN SILICO ANTI ATEROSCLEROSIS ACTIVITY OF

ANDROGRAPHOLIDE FROM SAMBILOTO ( ANDROGRAPHIS

PANICULATA (BURM. F NESS) N.M.P Susanti

1*, N.K. Warditiani

1, N.P.L.Laksmiani

1, I.M.A.G. Wirasuta

1

1. Pharmacy Departement, Faculty of Mathematic and Natural Science, Udayana University, Indonesia

Email :dekpitsusanti@unud.ac.id

Abstract Atherosclerosis, hardening of the blood vessels, can be treated through a process of RTC

(reverse cholesterol transport) involving proteins PPARα, PPARγ, and LXRα.

Andrographolide are compounds of Sambiloto (Andrographis paniculata (Burm.f Ness)

which have many pharmacological activity such as anti-cancer, anti-diabetic, anti-

inflammatory, anti-infective, antipyretic, and antiaterosclerotic activity. Molecular docking

is an in silico method used to determine the molecular activity of a compound. This study

aims to determine andrografolid activity as antiaterosclerotic with plaque-decay mechanism

trough RCT.

Molecular docking performed includes the preparation of 3D structures of proteins using

chimera 1.10.1 software, optimization of the 3D structure of andrographolide using

hyperchem 8 software (semi-empirical AM1), molecular docking method validation (RMSD

1-3 Å) and molecular docking to the protein PPARα (3ET1), PPARγ (3D6D), and LXRα

(2ACL) using Autodock 4.2. software. The lower the binding energy, the stronger and more

stable the bond between the protein and andrografolid.

The results showed that andrografolid is able to bind to proteins PPARα, PPARγ, and LXRα

with bond energy -8,74; -9,47; -10.34 kcal/mol respectively. It also has the same active site as

the native ligand shown by the hydrogen bonds formed between O atom of andrografolid

with H atom of SER280, ARG288 and THR300 amino acid of proteins. This can conclude

that andrografolid has activity as antiaterosklerosis with plaque decay mechanism trough

RCT.

Key word : Andrographolid, Atherosclerosis, RCT, In silico,

IN SILICO ANTIATEROSCLEROSIS ACTIVITY

OF ANDROGRAPHOLIDEFROM SAMBILOTO (

ANDROGRAPHIS PANICULATA(BURM. F NESS)

by Ni Made Pitri Susanti

Submission date: 13-Jan-2018 11:08AM (UTC+0700)Submission ID: 902347374File name: Abstrak_NMPS-revised.docx (18.03K)Word count: 263Character count: 1666

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GENERAL COMMENTS

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Result and discussion Preparation of protein PPARα (3ET1), PPARγ (3D6D), and LXRα (2ACL), downloaded from http://www.rcsb.org/pdb/home/home.do, aims to separate the native ligand and protein to provide space (pocket / cavity) during the docking process. The preparation is done using a chimera software 1.10.1. in order to obtain protein without native ligand (Figure 1) (A) (B)

Figure 1. Protein structure (A) and the native ligand (B)

IN SILICO ANTI ATEROSCLEROSIS ACTIVITY OF

ANDROGRAPHOLIDE FROM SAMBILOTO ( ANDROGRAPHIS

PANICULATA (BURM. F NESS) Ni Made P Susanti1, Ni Kadek Warditiani1, Ni Putu L. Laksmiani1, I M A G Wirasuta1

1Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Udayana, Bukit Jimbaran, Badung, 80363, Indonesia E-mail: dekpitsusanti@unud.ac.id

Optimization of Andrografolid was performed using semiempiris AM1 in Hyperchem 8 program with -5509.50 kcal / mol of energy obtained (Figure 2) . This energy shows the amount of energy required to break one mole of bonding species in a gaseous state. The lower the total energy of the molecule andrografolid, the more stable three-dimensional structure of andrographolide (Azam, 2012).

Figure 2. 3-dimensional structure of optimized Andrographolide Validation aims to determine the validity of docking methods used RMSD (Root Mean Square Deviation) as parameter. RMSD values 1-3 Å stated that the experimental crystal structures resembling the native ligand crystallography in the PDB (Protein Data Bank) so that the molecular docking method is valid and accurate. The RMSD result of native ligand validation on protein PPARα, PPARγ, and LXRα are 1.47; 2.9; and 2.06 Å respectively. Docking andrographolide on the protein PPARα, PPARγ, and LXRα using Autodock 4.2 software, and coordinates was set according to the coordinates of the native ligand. The results of andrografolid docking with protein PPARα, PPARγ, and LXRα shown in Figure 3.

(A) (B) (C)

(A) (B) (C) Figure 3. Interaction between andrografolid with protein PPARα (A), PPARγ (B), and LXRα (C)

Post docking result shows that binding energy of Andrografolid with PPARα (-8.74 Kcal/mol) and LXRα (-10.34 Kcal/mol) are greater than their native ligand (-9.82 Kcal/mol and -10.66Kcal/mol respectively). Binding energy between Andrografolid with PPARγ (-9.47 Kcal/mol) is smaller than the native ligand (-9.01 Kcal/mol). Andrografolid also has the same active site as the native ligand shown by the hydrogen bonds formed between O atom of andrografolid with H atom of SER280, ARG288 and THR300 amino acid of PPARα, PPARγ, and LXRα proteins respectively. These results prove that andrografolid from bitter plant (Andrographis paniculata (Burm.f) .Ness) can form bonds with proteins PPARα, PPARγ and LXRα that play a role in the RCT process.

Conclusion Andrografolid from bitter plant (Andrographis paniculata (Burm.f) .Ness) has activity as antiaterosklerosis with fatty plaque decay mechanism through RCT (reverse cholesterol transport).

Acknowledgements

This research was supported by Ministry of Research, Technology and Higher Education of the Republic of Indonesia

abstract Atherosclerosis, hardening of the blood vessels, can be treated through a process of RTC (reverse cholesterol transport) involving proteins PPARα, PPARγ, and LXRα. Andrographolide are compounds of Sambiloto (Andrographis paniculata (Burm.f Ness) which have many pharmacological activity such as anti-cancer, anti-diabetic, anti-inflammatory, anti-infective, antipyretic, and antiaterosclerotic activity. Molecular docking is an in silico method used to determine the molecular activity of a compound. This study aims to determine andrografolid activity as antiaterosclerotic with plaque-decay mechanism trough RCT. Molecular docking performed includes the preparation of 3D structures of proteins using chimera 1.10.1 software, optimization of the 3D structure of andrographolide using hyperchem 8 software (semi-empirical AM1), molecular docking method validation (RMSD 1-3 Å) and molecular docking to the protein PPARα (3ET1), PPARγ (3D6D), and LXRα (2ACL) using Autodock 4.2. software. The lower the binding energy, the stronger and more stable the bond between the protein and andrografolid. The results showed that andrografolid is able to bind to proteins PPARα, PPARγ, and LXRα with bond energy -8,74; -9,47; -10.34 kcal/mol respectively. It also has the same active site as the native ligand shown by the hydrogen bonds formed between O atom of andrografolid with H atom of SER280, ARG288 and THR300 amino acid of proteins. This can conclude that andrografolid has activity as antiaterosklerosis with plaque decay mechanism trough RCT. Keywords : Andrographolid, Atherosclerosis, RCT, In silico

Methods Native ligand of the protein PPARα, PPARγ and LXRα obtained from http://www.rcsb.org/pdb/home /home.do. removed by Chimera 1.10.1 software to provide space (pocket / cavity), to determine the shape of the pocket, coordinate pocket, binding site center and radius cavity. Andrographolide structure is optimized by using Hyperchem 8 with semi-empirical AM1 method.. Validation of molecular docking method carried out by redocking native ligands to proteins using Autodock 4.2 software. Docking method is valid if the value of RMSD (Root Mean Square Distances) 1-3 Å. The result of docking Andrographolide to PPARα, PPARγ and LXRα using Autodock 4.2. will show the conformation of compounds with the lowest binding energy to the target protein.

Introduction Atherosclerosis is the underlying pathology of CHD (Coronary Heart Disease), where the presence of atherosclerotic plaque will cause constriction of blood vessels and inhibit blood flow to the heart (Cavallari and Robert, 2008). Atherosclerosis is hardening of the arteries caused by the accumulation of fatty deposits and other substances so that the lumen of blood vessels becomes narrow and its elasticity decreases resulting in disruption of blood flow (Ross, 1999). Atherosclerosis treatment can be done through the decay of atherosclerotic plaque through a process of RCT (reverse cholesterol transport) mediated by HDL (High-density lipoprotein). Andrografolid from the bitter plant (Andrographis paniculata Nees) is is one diterpene lactone class that have various pharmacological activities such as antioxidants, analgesics, lowering blood sugar, triglycerides and LDL, and antiaterosklerosis (Lin et al., 2009; Nugroho et al., 2012; Azlan et al., 2013). Based on this background, this research will be carried out molecular docking andrografolid of Andrographis paniculata with target proteins PPARα, PPARγ, and LXRα triggered ABCA1 and ABCG1 expression that play a role in RTC process.

References Azlan, A., Younis, L., Mahmud, N.H. and Dardiri, N.A. 2013. European International Journal of Science and Technology. Vol. 2(2). P. 1-6. Cavallari, L.H and Robert J.D. 2008. Ischemic Heart Disease. In: Pharmacotherapy Principles and Practice. USA: The McGraw-Hill Companies. Lin, F.L., Wu, S.J. and Lee, S.C. 2009. Phytother Res. Vol. 23(7). P. 958-64. Nugroho, A.E., Andrie, M., Warditiani, K., Siswanto, E., Pramono, S. dan Lukitaningsih, E. 2012. Indian Journal Pharmacol. Vol. 44(3). P. 377-381. Ross, R. 1999. Aterosclerosis and Inflamatory Disease. The New England Journal of Medicine. Vol. 340. No. 2. P. 115-126.

IN SILICO ANTIATEROSCLEROSIS ACTIVITY

OF ANDROGRAPHOLIDEFROM SAMBILOTO (

ANDROGRAPHISPANICULATA (BURM. F NESS)

by Ni Made Pitri Susanti

Submission date: 13-Jan-2018 11:07AM (UTC+0700)Submission ID: 902347191File name: Poster_Pitri.pdf (824.32K)Word count: 1122Character count: 6265

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GENERAL COMMENTS

Instructor

PAGE 1

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