Journal of Islamic Medicine

Vol 4(1) (2020), Pages 1-7

e-ISSN: 2550-0074

Original research article

PREDICTING PHARMACOKINETIC PROFILES OF SUNFLOWER’S

(Helianthus annuus L.) ACTIVE COMPOUNDS USING IN SILICO
APPROACH

Alif Firman Firdausy1, Roihatul Muti’ah1 and Eka Kartini Rahmawati1

1
Department of Pharmacy, Faculty of Medicine and Health Sciences UIN Maulana Malik Ibrahim,
Malang, Indonesia
*Corresponding author
Email: aliffirman.firdausy@gmail.com

Abstract
Keywords: Introduction: Sunflower (Heliantus annuus L.) widely known as
Hellianuol medicinal plant for treating several diseases, such as
Sunflower hypertension, allergy, pain, inflammation, and cancer. It contains
Pharmacokinetic profie
various bioactive compounds which some of them were
pkCSM online tool
hellianuols. Hellianuols are a sesquiterpene lactones which
marked by benzene fused 6- to 8-membered cyclic ether ring
structure. To make sure that hellianuols were adequate for
development as a new chemical entities, we predicted some
pharmacokinetic parameters of several hellianuols compounds (A
to L) through in silico approach. Methods: We constructed 3
dimensional structures of hellianuol A, B, C, D, E, F, G, H, I, J, K
and L then generated the SMILE codes of each compound. These
codes then used as main material for running pkCSM online tool
to predict absorption, distribution, metabolism, and excretion
profile of each compounds. Results: Helianuols predicted to be
well absorbed in intestine (90.793% to 95.384% permeability),
skin (Log Kp: -2.662 to -3.570), and high permeability against
monolayer Caco-2 cell lines (LogPapp: 1.186 to 1.341 ×10-6cm/s).
Unfortunately, it had been predicted that hellianuols poorly
distributed in the body based on volume of distribution at steady
state (VDSS: 0.094 to 0.317) value. But its also predicted that most
of hellianuols had a capability to pass through blood-brain
barriers (LogBBB: up to 0.389) and penetrated into central
nervous system as well. Only hellianuol G, H and K predicted to
be metabolized by CYP1A2 inhibitor and only hellianuol A, B, D,
E and K metabolized by CYP2C19. Also predicted that hellianuols
were excreted in around 0.719 to 1.082 mg/kg/day. Conclusion:
Hellianuols contained in leaf aqueous extract of sunflower
predicted to be a good new pharmaceutical entities candidate
based on its pharmacokinetic profiles.

Alif Firman Firdausy, Roihatul Muti’ah and Eka Kartini 1

Rahmawati
 Predicting pharmacokinetic Profiles Of Sunflower’s (Helianthus annuus L.) Active Compounds Using In Silico
Approach

INTRODUCTION Using the SMILE string, we predicted

The discovery of new chemical absorption, distribution, metabolism and
entities originated from plants has excretion (ADME) profiles of hellianuol
attracted much attention in the last two A-L. The prediction of twelve compounds
decades. It is becoming more important to was conducted using pkCSM online tool
implement modern methodologies and (http://biosig.unimelb.edu.au/pkcsm/predi
innovative strategy for designing an ction).
effective, safe, and acceptable new drug
(1). Qualified drug must meet some RESULTS AND DISCUSSION
standards of pharmacokinetics aspects, The pharmacokinetic properties of
abbreviated with ADME (Absorption, hellianuol A-L according to pkCSM
Distribution, Metabolism, Excretion). It online tool are presented in Table 1.
takes more time and also costs for
conducting in vivo and in vitro data to Absorption
assure that drug candidates are good in Hellianuol A-L exhibited high value
absorption, distribution, metabolism, and (90.763% to 95.384%) of predicted %
excretion. Predicting pharmacokinetic human intestinal absorption as their
aspects through in silico and values are above 80% (12). Hellianuol A-
computational modelling is important L predicted to be skin permeable as their
nowadays, especially to cut off time and skin permeability constant values (−2.662
cost requirement of a new drug discovery to −3.570 logKp) are below -2.5 (13). The
(2). ability of hellianuols to transport through
Macias et al. were succesfully intestinal mucosa membrane were
isolated and elucidated 12 kinds of predicted by apparent permeabilites of
sesquiterpene compounds from aqueous Caco-2 cell line parameter (Papp) (14).
extract of Helianthus annuus L. cv. SH- According to US FDA, Papp values
222 leaves, namely: Hellianuol A, B, C, <1×10-6cm/s indicate poor permeability
D, E, F, G, H, I, J, K, and L (3,4). and Papp >10×10-6cm/s indicate high
Hellianuols structure marked with the permeability, then hellianuol A-L
-6
presence of benzenefused 6- to 8- exhibited 1.186 to 1.341 ×10 cm/s
membered cyclic ether ring so they are LogPapp (15), it could be predicted that
included in sesquiterpene compounds (5). hellianuol A-L were poorly permeable
Some hellianuol (B, G, H) have a through Caco-2 cell line. Another aspect
benzoxepine ring inside their structure. of absorption were predicted through
The structure of hellianuols A-L heliannuols interactions to P-glycoprotein
represented in Figure 1. According to (P-gp), a transporter protein that play
Kuntala et al., derivatives of benzoxepine several important roles during drug
showed various pharmacological effects absorption, especially for expelling
such as: antibacterial and anticancer molecules out of cells (16). Based on their
activity, anti-hypertension agent, estrogen structures, there are eight hellianuols (A,
receptor modulator and anti-HIV agent B, C, D, E, G, H, L) predicted to be the
(6–10). Hellianuols itself widely observed substrate of P-gp, thus only hellianuol F, I,
as natural herbicide agents due to its J and K could be absorbed without
herbicidal activities against wide range of extracted out of cells.
monocotyledons and dicotyledons (11).
Distribution
MATERIALS AND METHODS Steady state volume of distribution
The structure of twelve hellianuols (Vdss) is a pharmacokinetic parameter to
were designed using ChemBio2D Draw estimate drug distribution within tissues.
Ultra v12.0 (CambridgeSoft) and obtained The higher the Vdss value, the more drug
the SMILE string of each compound. concentration is distributed into the tissue

Alif Firman Firdausy, Roihatul Muti’ah and Eka Kartini 2

Rahmawati
 Predicting Pharmacokinetic Profiles Of Sunflower’s (Helianthus annuus L.) Active Compounds Using In
Silico
Approach

Hellianuol A Hellianuol B Hellianuol C

Hellianuol D Hellianuol E Hellianuol F

Hellianuol G Hellianuol H Hellianuol I

Hellianuol J Hellianuol K Hellianuol L

Figure 1. Chemical structures and common names of the 12 hellianuol compounds investigated in this
study.

than plasma (17). Vdss considered low if hellianuol C, E, F, I, J, and K predicted as

its logarithmic form under -0.15 (logVdss moderately distributed to the brain
< -0.15) and high if above 0.45 (logVdss > (LogBB < 0.3) (18). It is also predicted
0.45) (18). Hellianuols showed that hellianuol A, B, C, and D would
moderately distributed with logVdss shows such good in situ brain perfusions
values range between 0.094 – 0.317. result (logPS > -2), while only hellianuol
Based on pkCSM result, LogBB L showed low prediction value (LogPS= -
values of hellianuols vary between -0.616 3.189).
and 0.389. Hellianuol A, B, D, G, H, and PkCSM could predict how molecules
K have such chemical structures that are distributed within the body based on
allows them to readily cross the blood- their structure. From the data
brain barrier (LogBB > 0.3), while supplemented in Table 1, we predicted
that helainnuols could be well distributed CONCLUSION
in the body. It could be assumed as well Based on in silico pharmacokinetic
that some hellianuols would be distributed profiles study of hellianuol A-L contained
to the brain. Especially hellianuol A, B, in aqueous extract of Helianthus annuus L.
and D which have high values of LogBB cv. SH-222 leaves using pkCSM online
and LogPS, so they are predicted to tool, it can be concluded that overall
readily cross the blood-brain barrier and could be well absorbed through oral
penetrated directly into the central administration. Hellianuols were quite
nervous system (19,20). promising to be developed as a an
anticancer drug especially for brain
Metabolism cancer, as they were predicted to be able
Cytochrome P450s is an important to penetrated blood-brain barrier into
enzyme for xenobiotics metabolism in central nervous system. Their properties
liver. Two main subtype of cytochrome exhibited such a good pharmacokinetics
as well.
P450 are CYP2D6 and CYP3A4.
This study widely opens
Metabolism of hellianuols are predicted
opportunities for further research on
based on models for different CYP hellianuols, especially to produce more
isoforms (CYP2D6, CYP3A4, CYP1A2, accurate result prospectively in in vitro
CYP2C19, CYP2C9, CYP2D6, and and in vivo studies.
CYP3A4) (18,21). The results showed
that hellianuol G and H were predicted to ACKNOWLEDGEMENTS
be CYP1A2 inhibitor, and hellianuol A, We thank the Department of
B, D, and E were predicted to be Pharmacy, Faculty of Medicine and
CYP2C19 inhibitor. This suggested that Health Sciences UIN Maulana Malik
hellianuols may not metabolised directly Ibrahim Malang for providing us a good
in liver as they were not being the internet access to do our research.
substrate of Cytochrome P450 enzymes
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 Predicting pharmacokinetic Profiles Of Sunflower’s (Helianthus annuus L.) Active Compounds Using In Silico
Approach

Table 1. Predicted ADME properties of hellianuols

Hellianuol
Properties A B C D E F G H I J K L
Empirical C14H20O3 C15H20O3 C16H22O3 C15H22O3 C16H22O3 C15H20O4 C15H20O3 C15H20O3 C15H20O4 C15H20O4 C15H20O3 C15H22O4
formula
Molecular
weight (g/mol) 236.31 248.32 262.34 250.33 262.34 264.32 248.32 248.32 264.32 264.32 248.32 266.33
Absorption
Intestinal
absorption (% 90,793 91,239 91,473 90,763 91,369 94,255 93,800 93,800 92,542 92,542 93,593 95,384
absorbed)
Skin
permeability -3.21 -3,218 -3,241 -3,186 -3,215 -3,570 -2,942 -2,942 -3,314 -3,314 -2,662 -3,109
(log Kp)
Caco-2
permeability
(log Papp in 10-6 1.297 1,283 1,252 1,295 1,295 1,248 1,287 1,287 1,186 1,186 1,341 1,206
cm/s)
P-glycoprotein Yes Yes Yes Yes Yes No Yes Yes No No No Yes
substrate
P-glycoprotein No No No No No No No No No No No No
I inhibitor
P-glycoprotein No No No No No No No No No No No No
II inhibitor
Distribution
Vdss (log L/kg)
0.094 0,150 0,076 0,159 0,172 0,096 0,317 0,317 0,270 0,270 0,193 0,115
BBB
permeability 0.341 0,311 0,296 0,313 0,021 0,092 0,389 0,389 0,112 0,112 0,378 -0,616
(logBB)
Metabolism
CYP2D6 No No No No No No No No No No No No
substrate
CYP3A4 No No No No No No No No No No No No
substrate
CYP1A2 No No No No No No Yes Yes No No Yes No
inhibitor

Alif Firman Firdausy, Roihatul Muti’ah and Eka Kartini 6

Rahmawati
 Predicting Pharmacokinetic Profiles Of Sunflower’s (Helianthus annuus L.) Active Compounds Using In Silico
Approach

CYP2C19 Yes Yes No Yes Yes No No No No No Yes No

inhibitor
Properties Hellianuol
A B C D E F G H I J K L
CYP2D6
No No No No No No No No No No No No
inhibitor
CYP3A4
No No No No No No No No No No No No
inhibitor
Excretion
Total clearance
(log ml/min/kg) 0,947 1,011 1,082 0,948 1,078 0,895 0,905 0,905 0,719 0,719 0,974 0,824

Renal OCT2
No No No No No No No No No No No No
substrate
ADME, absorption, distribution, metabolism, excretion; Papp, apparent permeability coefficient; Kp, skin permeability constant; Vdss, volume of distribution at
steady state; BBB, blood-brain barrier; BB, blood-brain; CNS, central nervous system; PS, permeability-surface area; OCT2, organic cation transporter-2