Reza Mohammadhassan, Sepideh Fallahi, Zahra ......Reza Mohammadhassan, Sepideh Fallahi, Zahra...
Transcript of Reza Mohammadhassan, Sepideh Fallahi, Zahra ......Reza Mohammadhassan, Sepideh Fallahi, Zahra...
Reza Mohammadhassan, Sepideh Fallahi, Zahra Mohammadalipour
Page | 840
ADMET and pharmaceutical activity analysis of caffeic acid diversities by in silico tools
Reza Mohammadhassan 1, *
, Sepideh Fallahi 2
, Zahra Mohammadalipour 3
1 Plant Science Department, Amino Techno Gene Private Virtual Lab, Tehran, Iran 2Animal Science Department, Amino Techno Gene Private Virtual Lab, Tehran, Iran 3 Medical Science Department, Amino Techno Gene Private Virtual Lab, Tehran, Iran
*corresponding author e-mail address: [email protected] ABSTRACT
Caffeic acid diversities are widely considered as one of the most pharmaceutical secondary metabolites to study for treating a wide range
of disorders and diseases. In this paper, toxicity, ADME, and pharmaceutical activity of 16 compounds of the Caffeic acid diversities, are
analyzed by Toxtree software and Molinspiration website, respectively. According to the results, it can be concluded that Caffeoylmalic
acid and Dactylifric acid could be considered as the safest and the most applicable compounds. It might be suggested that modification
of molecular structures of Chlorogenic acid and Neochlorogenic acid could be useful for becoming low toxic and more applicable
compounds for oral consumption.
Keywords: Caffeic acid diversities; ADME; Toxicity; pharmaceutical activity; Lipinski's rule of five; in silico.
1. INTRODUCTION
Medicinal plants contain effective ingredients that can
physiologically influence on other organisms. These ingredients,
known as secondary metabolites that are biosynthesized in low
amount, usually less than 1 percent of plant dried weight.
Generally, they are also low-molecular-weight compounds, less
than 150 KDa [1]. Secondary metabolites play remarkable
ecological roles in plants. The metabolites are widely used as bio-
herbicide, flavoring agents, natural colors and medication in
biotechnology [2]. Antioxidants, such as Flavonoids, are the most
remarkable metabolites [3]. Caffeic acid diversities are classified
as the most common and applicable Flavonoids that contain
phenolic and acrylic functional groups [4]. There can be found
caffeic acid diversities in many medicinal plants, such as
Echinacea (Echinacea purpurea) [5], tea (Camellia sinensis) [6]
and Eucalyptus (Eucalyptus globulus) [7]. Caffeic acid
biosynthesis is promoted by coumaroyl ester hydroxylating quinic
acid. Then, chlorogenic acid and caffeic acid ester are
consequently biosynthesized. The compounds are precursors of
other caffeic acid diversities biosynthesis [8].
These compounds have antibacterial, anti –mutagenic, and
antiviral effects. There are many studies to demonstrate medicinal
effects, particularly antiviral such as inhibiting replication of HIV
[5], hepatitis B virus (HBV) and hepatitis C virus as two fatal
factors to cause viral hepatitis [9]. Many studies have been
reported strong anti-oncologic activities of the compounds on
many types of cancer, particularly breast cancer [10], oral cancer
[11] and prostate cancer [12]. Caffeic acid diversities can also
elicit neuroprotective activity to prevent neurodegeneration [13]
especially in Parkinson as the intense and progressive movement
disorder, caused by the death of neurons in the brain [14].
In pharmacology and pharmacokinetics, ADMET
(Absorption, Distribution, Metabolism, Excretion, and Toxicity)
describes the condition of the pharmaceutic compounds within an
organism. All the four criteria and kinetic effect on the pharmaceutic activity and function of the candidate compound as a
medicine, consequently tissues [15]. Biological/pharmaceutical
activity describes the favorable and detrimental effects of the
candidate medicine on an organism. Among several characteristics
of each compound, bioactivity plays prominent roles to employ it
as a medication. Whilst, biochemical compounds probably show
some detrimental and toxic effects which perhaps prevent to be
applied in pharmacology [16]. Both bioactivity and ADMET can
be analyzed by Lipinski’s rule of five. This rule, also known as the
Pfizer's rule of five, is employed to investigate drug-likeness, as
well as determine the characteristics of the chemical compounds
with specific biological and pharmaceutical activity for feasible
oral consumption [17]. There can be found many studies about
analyzing ADMET and bioactivity of herbal compounds by
bioinformatic tools. Mekha Mohan et al. (2015) has analyzed
ADMET and pharmaceutical activity of phytochemicals which can
be extracted from Phyllanthus niruri [18]. Also, six alkaloids
including oliveroline, coptisine, aristolactam, and piperine, have
been evaluated for ADMET and biological activity factors by in
silico tools [19], as well as velutin, galugin, chrysin, and zileuton
[20]. Tiwari et al. (2018) have computationally analyzed
biological activity and ADMET of nineteen secondary metabolites
[21].
Constantinescu et al. (2019) were also reported in silico
study about ADMET and bioactivity of 44 previously
biosynthesized compounds such as thiazole chalcones, flavanones,
flavones, 3-hydroxyflavones, and their acetylated diversities [22].
In the study, ADMET and pharmaceutical activity of 16 diversities
of caffeic acid were analyzed by chemoinformatic tools.
2. MATERIALS AND METHODS
2.1. Data collecting. ChemSpider (http://www.chemspider.com/),
as a huge database for chemical compounds [23], was used to
collect the information of the caffeic acid diversities.
2.2. ADME analysis. ADME of these derivatives, was analyzed
by Molinspiration website (http://www.molinspiration.com/),
regarding chemical structure [23].
Volume 9, Issue 1, 2020, 840 - 848 ISSN 2284-6808
Open Access Journal Received: 15.01.2020 / Revised: 18.02.2020 / Accepted: 19.02.2020 / Published on-line: 21.02.2020
Original Research Article
Letters in Applied NanoBioScience https://nanobioletters.com/
https://doi.org/10.33263/LIANBS91.840848
ADMET and pharmaceutical activity analysis of caffeic acid diversities by in silico tools
Page | 841
2.3. Toxicity analysis. The toxicity of the compounds was
estimated by ToxTree software (http://toxtree.sourceforge.net).
This software compares an intended chemical substance with
detected and known toxic compounds [23].
2.4. Bioactivity analysis. Molinspiration website was also applied
for analyzing bioactivity of caffeic acid diversities [23].
3. RESULTS
Lipinski’s rule of five defines that, candidate compound for
an oral active medication must have no more than one violation of
these following criteria: 1. logP is no more than 4.15. 2. Molecular
weight is no more than 500. 3. It should have less than five donors
of the hydrogen bond 4. It should have less than ten acceptors of
the hydrogen bond. logP defines candidate oral drug suitability.
Lower molecular weight is considered for the ability of diffusion.
The amounts of the Hydrogen bond acceptors and donors can
determine water solubility [17]. For the analysis of the bioactivity,
a lower score than -5.0, between 0.0 and -5.0 and a higher score
than 0.0 respectively mean active, moderately active and inactive
[24]. It also seems that score between 2.0 and 4.0 is higher active
(blue range) and more than 4.0 means the highest active (green
range).
Table 1. Bioactivity and ADMET analysis of Caffeic acid.
AMDE
volume nviolations nOHNH nON Molecular Weight natoms TPSA miLogP
154.50 0 3 4 180.16 13 77.75 0.94
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase inhibitor Ion channel
modulator
GPCR
ligand
-0.09 -0.79 -0.10 -0.81 -0.23 -0.48
Table 2. Bioactivity and ADMET analysis of Ethyl caffeate.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
188.83 0 2 4 208.2 15 66.76 1.93
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
-0.22 -0.71 -0.18 -0.78 -0.29 -0.59
Table 3. Bioactivity and ADMET analysis of Methyl caffeate.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
172.03 0 2 4 194.1 14 66.76 1.56
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Prote
ase
inhibi
tor
Nuclear
receptor
ligand
Kinase inhibitor Ion channel
modulator
GPCR
ligand
-0.22 -0.78 -0.26 -0.82 -0.32 -0.62
3.1. Caffeic acid.
All these criteria for caffeic acid AMDE are in the proper
range, regarding the Lipinski’s rules of five. In other word, there is
no violation of Lipinski’s rule of five. Moreover, the toxic hazard
of the compound was estimated low; as well as classified I.
Enzyme inhibitor score (-0.09) is considered as the highest
biological activity of Caffeic acid (Table 1).
Reza Mohammadhassan, Sepideh Fallahi, Zahra Mohammadalipour
Page | 842
3.2. Ethyl caffeate.
There is no violation of the rule of five. Toxic hazard is
estimated low and also classified I. The highest score of
pharmaceutical activity belongs to enzyme inhabitation (-0.22)
(Table 2).
3.3. Methyl caffeate.
There cannot be found any violation of Lipinski’s rule of
five. Methyl caffeate was classified as a low toxic hazard
compound, class I. Enzyme inhabitation of this compound was
scored -0.22, as the highest biological activity (Table 3).
Many studies have demonstrated the pharmaceutical
activities of caffeic acid diversities. Antidiabetic effects of caffeic
acid are caused by the inhabitation of α-amylase and α-glycosidase
[25]. The compound can also suppress lipid accumulation by
inhabiting PPARγ protein expression [26]. Methyl caffeate can
induce apoptosis by activation of caspase [27], as well as reduce
low inflammation related to age which causes neurodegenerative
diseases [28] such as Parkinson [14]. Ethyl caffeate can
increasingly regulate caspase 3 and caspase 9 in tumor tissues [29]
and also inhibits immune response and signaling, related to
interferon γ, to cure arthritis, induced by collagen [30]. The
current results show that the above mentioned caffeic acid
diversities are proper for oral consumption with low toxic hazard.
But, against previous studies and the results, there are no desirable
biological activities for these compounds, regarding the present
analysis.
3.4. Echinacoside.
Topological polar surface area (TPSA), Molecular weight
(MW), Hydrogen bond donors and acceptors of Echinacea are
respectively 324.44, 786.73, 12 and 20. So, there can be found
three violations of the rule of five. Toxic hazard is also classified
high and class III. The highest bioactivity of the compound is the
estimated protease inhibitor (-0.88) (Table 4).
Table 4. Bioactivity and ADMET analysis of Echinacoside.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
664.6 3 12 20 786.7 55 324.4 -2.15
Toxicity
Toxic Hazard class Toxic Hazard
III High
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
-1.56 -0.88 -2.04 -1.99 -2.44 -1.28
Table 5. Bioactivity and ADMET analysis of Cynarine.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
431.08 3 7 12 516.4 37 211.2 1.42
Toxicity
Toxic Hazard class Toxic Hazard
III High
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.42 0.21 0.50 -0.01 0.04 0.18
3.5. Cynarine.
TPSA, MW, Hydrogen bond donor and acceptor scores
of Cynarine are respectively 211.2, 516.4, 12 and 7. So, there are
three violations of Lipinski’s rule of five. The toxic hazard is high
and classified III. Nuclear receptor, protease and enzyme
inhibitors were scored as the highest pharmaceutical activities, in
order to 0.50, 0.21 and 0.42 (Table 5).
3.6. p-Coumaric acid glucoside.
Although there is no violation of the rule, the toxic
hazard was categorized class III and high. Nuclear receptor ligand
and enzyme inhibitor are respectively estimated 0.30 and 0.42 as
the highest pharmaceutical activities of p-Coumaric acid glucoside
(Table 6).
3.7. Caftaric acid Conj.
AMDE Analysis of Caftaric acid Conj. (conjugated with
glutathione) shows 3 violation of the rule including TPSA (320.4),
MW (617.5), Hydrogen bond donors (18) and acceptors (11). The
hazard of the toxicity is high for the compound, consequently,
categorized in class III. Protease inhabitation reached just the
highest score of biological activity (Table 7).
ADMET and pharmaceutical activity analysis of caffeic acid diversities by in silico tools
Page | 843
All reported studies on Caftaric acid conj. are in the wine
production field, not pharmacology [31]. In the contrary, there are
many pharmacological studies for p-Coumaric acid glucoside,
Cynarine, and Echinacoside. p-Coumaric acid glucoside can
effect as same as dexamethasone on hypoxic cerebral edema [32];
as well as normobaric hypoxic pulmonary edema. So, the
compound could improve lung barrier [33] and blood-brain-barrier
and inhibit oxidative stress and, consequently, inflammation [32].
According to previous studies, Cynarine shows antioxidant,
antichlorogenic, antiradical [34] and antigenotoxic effects [35].
Echinacoside can effect as a neuroprotective compound against
neuroinflammation and signals related to Parkinson [36]. In other
words, this compound can protect neurons against apoptosis
induced by methyl-4-phenylpyridinium in the disorder [37]. The
present results could confirm the high pharmaceutical activity of
the above mentioned natural compounds, except Echinacoside,
particularly nuclear receptors ligands and inhabitation protease
and enzymes in blue level; but, just p-Coumaric acid glucoside is a
suitable compound for oral consumption, with regards to ADME
analysis. Nevertheless, all these compounds are highly toxic.
Table 6. Bioactivity and ADMET analysis of p-Coumaric acid glucoside.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
278.6 0 5 8 326.3 23 136.6 -0.36
Toxicity
Toxic Hazard class Toxic Hazard
III High
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.42 0.07 0.30 -0.12 -0.01 0.17
Table 7. Bioactivity and ADMET analysis of Caftaric acid Conj.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
498.19 3 11 18 617.5 42 320.4 -5.19
Toxicity
Toxic Hazard class Toxic Hazard
III High
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.18 0.38 -0.09 -0.32 -0.35 0.17
3.8. Chicoric acid.
Score of TPSA, Hydrogen donors and acceptors of
Chicoric acid are estimated 208.1, 12 and 6 respectively.
Consequently, just one violation of the rule of five could be found.
Besides, the toxic hazard of the compound was predicted as low;
as well as classified I. Nuclear receptor ligand (0.29) score shows
the highest bioactivities of the compound (Table 8).
3.9. Caftaric acid.
There can be found just one violation of the rule, caused by
score of TPSA (161.5). In addition, the toxic hazard of the
compound was predicted low and classified I. The highest
biological activities of the compound are nuclear receptor ligand
(0.41) and enzyme inhibitor (0.26) (Table 9).
3.10. Coutaric acid.
There are no violations of Lipinski’s rules of five for
Coutaric acid. The toxic hazard of the compounds was estimated
low, as well as class I. Nuclear receptor ligand (0.44) and enzyme
inhibitor (0.28), are considered as the highest biological activities
of this compound (Table 10).
3.11. Fertaric acid.
The violation of the rules was scored 0 for Fertaric acid.
The hazard of the toxicity is low and classified I. Nuclear receptor
ligand (0.34) was determined as the highest biological activity of
the compound (Table 11).
3.12. Caffeic acid phenethyl ester.
Violation of the rule of five was scored 0 for Caffeic acid
phenethyl ester. The compound was also estimated as a low toxic
hazard (class I). Nuclear receptor ligand (0.26) is considered as the
highest biological activity of this compound (Table 12).
There are some studies to report anti-inflammatory
properties of Fertaric acid [38]; as well as protecting liver against
4-tert-octylphenol caused by hepatotoxicity [39]. Many studies
Reza Mohammadhassan, Sepideh Fallahi, Zahra Mohammadalipour
Page | 844
have also demonstrated anticarcinogenic, anti-inflammatory,
immunomodulatory, antimutagenic and antiviral activities of
Caffeic acid phenethyl ester [40]. The compound can also inhibit
metabolic enzymes, specifically Acetylcholinesterase and
Butyrylcolinesterase [41]. Several studies have shown anti-
inflammatory and antioxidant properties of Caftaric acid in gastric
ulcer induced by indomethacin [42] and also antidiabetic and
antihypertensive effects [43]. There are many reports to the
indicated antiviral activity of Chicoric acid against herpes simplex
(HSV), influenza and human immunodeficiency viruses (HIV)
[44] and also can induce apoptosis to inhibit human breast cancer
cells [45]. There cannot be found any research on pharmaceutical
activity of Coutaric acid. According to the present results, Caffeic
acid phenethyl ester, Fertaric acid and Coutaric acid exert no
violation of the rule. So, these three compounds can be orally
consumed. In contrast, there are one and two violations of Caftaric
acid and Chicoric acid, respectively. Caffeic acid phenethyl ester
and Fertaric acid are biologically active to bind nuclear receptors.
Coutaric acid, Caftaric acid and Chicoric acid are also
pharmaceutical active for binding nuclear receptors and inhibiting
enzymes. Nevertheless, all these five caffeic acid diversities are
classified as low toxic compounds.
Table 8. Bioactivity and ADMET analysis of Chicoric acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
385.9 2 6 12 474.3 34 208.1 1.27
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.13 -0.03 0.29 -0.15 -0.06 0.05
Table 9. Bioactivity and ADMET analysis of Caftaric acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
251.14 1 5 9 312.2 22 161.5 -0.61
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.26 -0.05 0.41 -0.29 -0.12 0.04
Table 10. Bioactivity and ADMET analysis of Coutaric acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
243.12 0 4 8 296.2 21 141.3 -0.12
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.28 -0.06 0.44 -0.30 -0.10 0.03
ADMET and pharmaceutical activity analysis of caffeic acid diversities by in silico tools
Page | 845
Table 11. Bioactivity and ADMET analysis of Fertaric acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
268.67 0 4 9 326.2 23 150.5 -0.3
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.19 -0.10 0.34 -0.28 -0.19 0.00
Table 12. Bioactivity and ADMET analysis of Caffeic acid phenethyl ester.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
260.48 0 2 4 284.3 21 66.76 3.36
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.11 -0.08 0.26 -0.15 -0.04 0.01
3.13. Chlorogenic acid.
There can be found just a violation of the rule of five for
TPSA (164.7). Toxic Hazard was estimated as intermediate and
classified II. The compound is biologically active as GPCR ligand
(0.29), nuclear receptor ligand (0.74), protease (0.27) and enzyme
inhibitor (0.26) (Table 13).
3.14. Neochlorogenic acid.
Hydrogen acceptors of Neochlorogenic acid were
calculated 6 that it is considered as a violation of the rule. The
toxic hazard of the compound was estimated as intermediate, class
II. Enzyme inhibitor (0.74) and nuclear receptor ligand (0.62)
show the highest bioactivity of this compound; then GPCR ligand
(0.29) and protease inhibitor (0.27) (Table 14).
3.15. Caffeoylmalic acid.
There is no violation of the rule for Caffeoylmalic acid.
Toxic Hazard was classified I; as well as estimated low toxicity.
The highest bioactivity of the compound is found for nuclear
receptor ligand and enzyme inhibitor, 0.52 and 0.43 respectively
(Table 15).
3.16. Dactylifric acid.
There cannot be found any violation of the rule of five.
Toxic hazard was estimated intermediate and classified II. The
highest biological activities belong to the nuclear receptor ligand
(0.61) and enzyme inhibitor (0.52) (Table 16).
Table 13. Bioactivity and ADMET analysis of Chlorogenic acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
296.27 1 5 9 354.3 25 164.7 -0.45
Toxicity
Toxic Hazard class Toxic Hazard
II Intermediate
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.62 0.27 0.74 -0.00 0.14 0.29
Reza Mohammadhassan, Sepideh Fallahi, Zahra Mohammadalipour
Page | 846
Table 14. Bioactivity and ADMET analysis of Neochlorogenic acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
296.27 1 6 9 354.3 25 164.7 -0.45
Toxicity
Toxic Hazard class Toxic Hazard
II Intermediate
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.62 0.27 0.74 -0.00 0.14 0.29
Table 15. Bioactivity and ADMET analysis of Caffeoylmalic acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
243.10 0 4 8 296.2 21 141.3 0.31
Toxicity
Toxic Hazard class Toxic Hazard
I Low
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.43 0.16 0.52 -0.15 -0.01 0.19
Table 16. Bioactivity and ADMET analysis of Dactylifric acid.
AMDE
volume nviolations nOHNH nON MW natoms TPSA miLogP
282.36 0 5 8 336.3 24 144.5 0.31
Toxicity
Toxic Hazard class Toxic Hazard
II Intermediate
Biological activity
2D Structure Enzyme
inhibitor
Protease
inhibitor
Nuclear
receptor
ligand
Kinase
inhibitor
Ion channel
modulator
GPCR
ligand
0.52 0.15 0.61 -0.14 0.18 0.15
There could not be found any pharmacological studies on
Caffeoylmalic acid and Dactylifric acid. But according to the
results, Caffeoylmalic acid is low toxic and high bioactive
compounds, especially as more highly activity to bind nuclear
receptors and most enzyme inhibitory. Dactylifric acid also exerts
moderate toxicity and green range activity for both binding
nuclear receptors and inhibiting enzymes. Many studies have
demonstrated the antidiabetic effects of Chlorogenic acid by
inhibiting α-amylase and α-glycosidase [25]. The compound can
activate caspase to induce apoptosis in human renal cell carcinoma
[46] and also inhibit reverse transcriptase activity of HIV-1 [47].
Other studies reported the antioxidant activity of
Neochlorogenic acid. It can also inhibit α-glycosidase [48] and the
activity of the influenza virus [49]. Moreover, the compound
exerts neuroprotective effects by inhibiting the pathway of pro-
inflammation in activated microglia cells [50]. The present results
demonstrated the same properties for both Chlorogenic acid and
Neochlorogenic acid. They are classified as intermediate toxic
compounds, with just one violation of the rule of five, caused by
six hydrogen binding acceptors. Nevertheless, they are highly
pharmaceutically active, particularly binding.
4. CONCLUSIONS
Conclusively, Caffeoylmalic acid and Dactylifric acid are
the safest and the most applicable compounds between all sixteen
analyzed caffeic acid diversities, although there are not any studies
to report the pharmaceutical activity of Caffeoylmalic acid and
Dactylifric acid. Moreover, Chlorogenic acid and Neochlorogenic
acid, with the same characteristics can be considered as two potent
ADMET and pharmaceutical activity analysis of caffeic acid diversities by in silico tools
Page | 847
drug due to their high bioactivity. But their moderate toxicity and
a violation of the rule maybe play a role as the restriction factors
for becoming a potent drug. It can be expected to modify
molecular structures of both compounds to decrease the toxicity
level and the violation.
5. REFERENCES
1. Dutra, R.C.; Campos, M.M.; Santos, A.R.; Calixto, J.B.
Medicinal plants in Brazil: Pharmacological studies, drug
discovery, challenges and perspectives.
Pharmacological research 2016, 112, 4-29,
https://doi.org/10.1016/j.phrs.2016.01.021.
2. Delcheh, K.S.; Kashefi, B.; Mohammadhassan, R. A review
optimization of tissue culture medium medicinal plant: Thyme.
Int J Farm Alli Sci 2014, 3, 1015-1019.
3. Akhavan, S.; Kashefi, B.; Mojdehi, S.R.; Delcheh, K.S.;
Mohammadhassan, R. Application of pistachio (Pistacia sp.)
extract in Morphine Withdrawal Syndrome improvement: A
review. National Conferences on Scientific Approach in Green
Gold Industry, Pistachio. Damghan, Iran, 2015.
4. Sarwar, T.; Ishqi, H.M.; Rehman, S.U.; Husain, M.A.;
Rahman, Y.; Tabish, M. Caffeic acid binds to the minor groove
of calf thymus DNA: A multi-spectroscopic, thermodynamics
and molecular modelling study. International journal of
biological macromolecules 2017, 98, 319-328,
https://doi.org/10.1016/j.ijbiomac.2017.02.014.
5. Mohammadhassan, R.; Akhavan, S.; Mahmoudi, A.;
Khalkhali, A.; Barzin, R. Antiviral activity of Echinacea
(Echinacea purpurea). International Journal of Biology,
Pharmacy and Allied Sciences 2016, 5, 999-1005.
6. Pardau, M.D.; Pereira, A.S.; Apostolides, Z.; Serem, J.C.;
Bester, M.J. Antioxidant and anti-inflammatory properties of
Ilex guayusa tea preparations: a comparison to Camellia sinensis
teas. Food & function 2017, 8, 4601-4610,
https://doi.org/10.1039/c7fo01067b.
7. Fernández-Agulló, A.; Freire, M.S.; González-Álvarez, J.
Effect of the extraction technique on the recovery of bioactive
compounds from eucalyptus (Eucalyptus globulus) wood
industrial wastes. Industrial Crops and Products 2015, 64, 105-
113, https://doi.org/10.1016/j.indcrop.2014.11.031.
8. Heleno, S.A.; Martins, A.; Queiroz, M.J.R.; Ferreira, I.C.
Bioactivity of phenolic acids: Metabolites versus parent
compounds: A review. Food chemistry 2015, 173, 501-513,
https://doi.org/10.1016/j.foodchem.2014.10.057.
9. Akhavan, S.; Kashefi, B.; Aghayari N.; Delcheh, K.S.;
Mohammadhassan, R. Application of pistachio (Pistacia sp.)
derivatives in liver diseases improvement: A review. National
Conferences on Scientific Approach in Green Gold Industry,
Pistachio. Damghan, Iran. 2015.
10. Rosendahl, A.H.; Perks, C.M.; Zeng, L.; Markkula, A.;
Simonsson, M.; Rose, C.; Jernström, H. Caffeine and caffeic
acid inhibit growth and modify estrogen receptor and insulin-
like growth factor I receptor levels in human breast cancer.
Clinical Cancer Research 2015, 21, 1877-1887,
https://doi.org/10.1158/1078-0432.CCR-14-1748.
11. Kuo, Y.Y.; Jim, W.T.; Su, L.C.; Chung, C.J.; Lin, C.Y.; Huo,
C.; Wang, B.J. Caffeic acid phenethyl ester is a potential
therapeutic agent for oral cancer. International journal of
molecular sciences 2015, 16, 10748-10766,
https://doi.org/10.3390/ijms160510748.
12. Russo, G.; Campisi, D.; Di Mauro, M.; Regis, F.; Reale, G.;
Marranzano, M.; Morgia, G. Dietary Consumption of Phenolic
Acids and Prostate Cancer: A Case-Control Study in Sicily,
Southern Italy. Molecules 2017, 22, 2159,
https://doi.org/10.3390/molecules22122159.
13. Zaitone, S.A.; Ahmed, E.; Elsherbiny, N.M.; Mehanna, E.T.;
El-Kherbetawy, M.K.; ElSayed, M.H.; Moustafa, Y.M. Caffeic
acid improves locomotor activity and lessens inflammatory
burden in a mouse model of rotenone-induced nigral
neurodegeneration: Relevance to Parkinson’s disease therapy.
Pharmacological Reports 2019, 71, 32-41,
https://doi.org/10.1016/j.pharep.2018.08.004.
14. Ramedani, B.; Akhavan, S.; Mohammadhassan, R.;
Tutunchi, S.; Khazaei, A. Evaluation of DISC1 Gene rs3738401
Polymorphism in Iranian Parkinson Patients affected by type 2
Diabetes. Bull. Env. Pharmacol. Life Sci 2015, 4, 20-23.
15. Zhong, F.; Xing, J.; Li, X.; Liu, X.; Fu, Z.; Xiong, Z.; Li, F.
Artificial intelligence in drug design. Science China Life
Sciences 2018, 61, 1191-1204.
16. Razik, A.; Adly, F.; Berhal, C.; Moussaid, M.; Elamrani,
A.A.; Moussaid, H.; Loutfi, M. Comparative Study of the
Pharmaceutical Activity of two plants of the Moroccan
Spontaneous Flora: Mentha Pulegium (L) and Marrubium
Vulgare (L.)(Lamiaceae). International Journal of Scientific
Research in Science and Technology 2015, 1, 86-90.
17. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J.
Experimental and computational approaches to estimate
solubility and permeability in drug discovery and development
settings. Advanced drug delivery reviews 2012, 64, 4-17,
https://doi.org/10.1016/j.addr.2012.09.019.
18. Mohan, M.; Priyanka, J.; Valsalan, R.; Nazeem, P.A.
Molecular docking studies of phytochemicals from Phyllanthus
niruri against Hepatitis B DNA Polymerase. Bioinformation
2015, 11, 426, https://dx.doi.org/10.6026%2F97320630011426.
19. Singh, S.; Das, T.; Awasthi, M.; Pandey, V.P.; Pandey, B.;
Dwivedi, U.N. DNA topoisomerase‐directed anticancerous
alkaloids: ADMET‐based screening, molecular docking, and
dynamics simulation. Biotechnology and applied biochemistry
2016, 63, 125-137, https://doi.org/10.1002/bab.1346.
20. Singh, S.; Awasthi, M.; Pandey, V.P.; Dwivedi, U.N.
Lipoxygenase directed anti-inflammatory and anti-cancerous
secondary metabolites: ADMET-based screening, molecular
docking and dynamics simulation. Journal of Biomolecular
Structure and Dynamics 2017, 35, 657-668,
https://doi.org/10.1080/07391102.2016.1159985.
21. Tiwari, V.; Meena, K.; Tiwari, M. Differential anti-microbial
secondary metabolites in different ESKAPE pathogens explain
their adaptation in the hospital setup. Infection, Genetics
and Evolution 2018, 66, 57-65,
https://doi.org/10.1016/j.meegid.2018.09.010.
22. Constantinescu, T.; Lungu, C.N.; Lung, I. Lipophilicity as a
Central Component of Drug-Like Properties of Chalchones and
Flavonoid Derivatives. Molecules 2019, 24, 1505,
https://doi.org/10.3390/molecules24081505.
23. Van Noorden, R. Chemistry’s web of data expands. Nature
News 2012, 483, 524, https://doi.org/10.1038/483524a.
24. Joshi, A.; Kumar, R.; Sharma, A. Molecular Docking
Studies, Bioactivity Score Prediction, Drug Likeness Analysis of
GSK-3 β Inhibitors: A Target Protein Involved in Alzheimer’s
Disease. Biosciences Biotechnology Research Asia 2018, 15,
455-467, https://doi.org/10.13005/bbra/2650.
25. Oboh, G.; Agunloye, O.M.; Adefegha, S.A.; Akinyemi, A.J.;
Ademiluyi, A.O. Caffeic and chlorogenic acids inhibit key
enzymes linked to type 2 diabetes (in vitro): a comparative
study. Journal of Basic and Clinical Physiology and
Pharmacology 2015, 26, 165-170, https://doi.org/10.1515/jbcpp-
2013-0141
26. Lutfi, E.; Babin, P.J.; Gutiérrez, J.; Capilla, E.; Navarro, I.
Caffeic acid and hydroxytyrosol have anti-obesogenic properties
Reza Mohammadhassan, Sepideh Fallahi, Zahra Mohammadalipour
Page | 848
in zebrafish and rainbow trout models. PloS one 2017, 12,
https://doi.org/10.1371/journal.pone.0178833.
27. Balachandran, C.; Emi, N.; Arun, Y.; Yamamoto, Y.; Ahilan, B.;
Sangeetha, B.; Al-Dhabi, N.A. In vitro anticancer activity of methyl
caffeate isolated from Solanum torvum Swartz. fruit. Chemico-
biological interactions 2015, 242, 81-90,
https://doi.org/10.1016/j.cbi.2015.09.023.
28. Lim, H.; Park, B.K.; Shin, S.Y.; Kwon, Y.S.; Kim, H.P. Methyl
caffeate and some plant constituents inhibit age-related inflammation:
effects on senescence-associated secretory phenotype (SASP)
formation. Archives of pharmacal research 2017, 40, 524-535,
https://doi.org/10.1007/s12272-017-0909-y.
29. Yuan, H.; Han, A.; Zhang, X. Radio-sensitizing effect of ethyl
caffeate on nasopharyngeal carcinoma CNE-2 cell line. Tropical
Journal of Pharmaceutical Research 2017, 16, 1857-1863,
http://dx.doi.org/10.4314/tjpr.v16i8.15.
30. Xu, S.; Zuo, A.; Guo, Z.; Wan, C. Ethyl caffeate ameliorates
collagen-induced arthritis by suppressing th1 immune response. Journal
of immunology research 2017, 2017,
https://doi.org/10.1155/2017/7416792.
31. Garrido, J.; Borges, F. Wine and grape polyphenols—A chemical
perspective. Food research international 2013, 54, 1844-1858,
https://doi.org/10.1016/j.foodres.2013.08.002.
32. Li, Y.; Han, J.; Zhang, Y.; Chen, Y.; Zhang, Y. Prophylactic effect
and mechanism of p-coumaric acid against hypoxic cerebral edema in
mice. Respiratory physiology & neurobiology 2019, 260, 95-104,
https://doi.org/10.1016/j.resp.2018.11.004.
33. Li, Y.; Han, J.; Chen, Y.; Chen, C.; Chu, B.; Zhang, Y. p-Coumaric
acid as a prophylactic measure against normobaric hypoxia induced
pulmonary edema in mice. Life sciences 2018, 211, 215-223,
https://doi.org/10.1016/j.lfs.2018.09.039.
34. Topal, M.; Gocer, H.; Topal, F.; Kalin, P.; Köse, L.P.; Gülçin, İ.;
Alwasel, S.H. Antioxidant, antiradical, and anticholinergic properties of
cynarin purified from the Illyrian thistle (Onopordum illyricum L.).
Journal of enzyme inhibition and medicinal chemistry 2016, 31, 266-
275, https://doi.org/10.3109/14756366.2015.1018244
35. Erikel, E.; Yuzbasioglu, D.; Unal, F. In vitro genotoxic and
antigenotoxic effects of cynarin. Journal of ethnopharmacology 2019,
266-275, https://doi.org/10.3109/14756366.2015.1018244.
36. Zhang, J.; Zhang, Z.; Xiang, J.; Cai, M.; Yu, Z.; Li, X.; Cai, D.
Neuroprotective effects of echinacoside on regulating the stress-active
p38MAPK and NF-κB p52 signals in the mice model of Parkinson’s
disease. Neurochemical research 2017, 42, 975-985,
https://doi.org/10.1007/s11064-016-2130-7.
37. Zhao, Q.; Yang, X.; Cai, D.; Ye, L.; Hou, Y.; Zhang, L.; Bai, Y.
Echinacoside protects against MPP+-induced neuronal apoptosis via
ros/atf3/chop pathway regulation. Neuroscience bulletin 2016, 32, 349-
362, https://doi.org/10.1007/s12264-016-0047-4.
38. Kamiya, T.; Tanimoto, Y.; Fujii, N.; Negishi, T.; Suzuki, T.;
Hatano, T.; Arimoto-Kobayashi, S. 2, 6-Dimethoxy-1, 4-benzoquinone,
isolation and identification of anti-carcinogenic, anti-mutagenic and
anti-inflammatory component from the juice of Vitis coignetiae. Food
and Chemical Toxicology 2018, 122, 172-180,
https://doi.org/10.1016/j.fct.2018.10.028.
39. Koriem, K.M.; Arbid, M.S. Fertaric Acid Protects from
Octylphenol-Related Hepatotoxicity in Rats: Biochemical, Molecular,
and Histopathological Studies. Journal of dietary supplements 2019, 16,
152-165, https://doi.org/10.1080/19390211.2018.1443190.
40. Erdemli, H.K.; Akyol, S.; Armutcu, F.; Akyol, O. Antiviral
properties of caffeic acid phenethyl ester and its potential application.
Journal of intercultural ethnopharmacology 2015, 4, 344,
https://dx.doi.org/10.5455%2Fjice.20151012013034.
41. Gülçin, İ.; Scozzafava, A.; Supuran, C.T.; Akıncıoğlu, H.; Koksal,
Z.; Turkan, F.; Alwasel, S. The effect of caffeic acid phenethyl ester
(CAPE) on metabolic enzymes including acetylcholinesterase,
butyrylcholinesterase, glutathione S-transferase, lactoperoxidase, and
carbonic anhydrase isoenzymes I, II, IX, and XII. Journal of enzyme
inhibition and medicinal chemistry 2016, 31, 1095-1101,
https://doi.org/10.3109/14756366.2015.1094470.
42. Tanyeli, A.; Ekinci, F.A.; Eraslan, E.; Güler, M.C.; Nacar, T. Anti-
oxidant and anti-inflamatuar effectiveness of caftaric acid on gastric
ulcer induced by indomethacin in rats. General physiology and
biophysics 2019, 38, https://doi.org/10.4149/gpb_2018035.
43. Chiou, S.Y.; Sung, J.M.; Huang, P.W.; Lin, S.D. Antioxidant,
antidiabetic, and antihypertensive properties of Echinacea purpurea
flower extract and caffeic acid derivatives using in vitro models.
Journal of medicinal food 2017, 20, 171-179,
https://doi.org/10.1089/jmf.2016.3790.
44. Langland, J.; Jacobs, B.; Wagner, C.E.; Ruiz, G.; Cahill, T. M.
Antiviral activity of metal chelates of caffeic acid and similar
compounds towards herpes simplex, VSV-Ebola pseudotyped and
vaccinia viruses. Antiviral research 2018, 160, 143-150,
https://doi.org/10.1016/j.antiviral.2018.10.021.
45. Torres, R.G.; Casanova, L.; Carvalho, J.; Marcondes, M.C.; Costa,
S.S.; Sola-Penna, M.; Zancan, P. Ocimum basilicum but not Ocimum
gratissimum present cytotoxic effects on human breast cancer cell line
MCF-7, inducing apoptosis and triggering mTOR/Akt/p70S6K
pathway. Journal of bioenergetics and biomembranes 2018, 50, 1-13,
https://doi.org/10.1007/s10863-018-9750-3.
46. Wang, X.; Liu, J.; Xie, Z.; Rao, J.; Xu, G.; Huang, K.; Yin, Z.
Chlorogenic acid inhibits proliferation and induces apoptosis in A498
human kidney cancer cells via inactivating PI 3K/Akt/mTOR signalling
pathway. Journal of Pharmacy and Pharmacology 2019, 7,
https://doi.org/10.1111/jphp.13095.
47. Tamayose, C.I.; Torres, P.B.; Roque, N.; Ferreira, M.J.P. HIV-1
reverse transcriptase inhibitory activity of flavones and chlorogenic acid
derivatives from Moquiniastrum floribundum (Asteraceae). South
African Journal of Botany 2019, 123, 142-146,
https://doi.org/10.1016/j.sajb.2019.02.005.
48. Baessa, M.; Rodrigues, M.J.; Pereira, C.; Santos, T.; da Rosa Neng,
N.; Nogueira, J.M.F.; Boukhari, S.A. A comparative study of the in
vitro enzyme inhibitory and antioxidant activities of Butea monosperma
(Lam.) Taub. and Sesbania grandiflora (L.) Poiret from Pakistan: New
sources of natural products for public health problems. South African
Journal of Botany 2019, 120, 146-156,
https://doi.org/10.1016/j.sajb.2018.04.006.
49. Ding, F.; Liu, J.; Du, R.; Yu, Q.; Gong, L.; Jiang, H.; Rong, R.
Qualitative and Quantitative Analysis for the Chemical Constituents of
Tetrastigma hemsleyanum Diels et Gilg Using Ultra-High Performance
Liquid Chromatography/Hybrid Quadrupole-Orbitrap Mass
Spectrometry and Preliminary Screening for Anti-Influenza Virus
Components. Evidence-Based Complementary and Alternative
Medicine 2019, 1-15, https://doi.org/10.1155/2019/9414926.
50. Kim, M.; Choi, S.Y.; Lee, P.; Hur, J. Neochlorogenic acid inhibits
lipopolysaccharide-induced activation and pro-inflammatory responses
in BV2 microglial cells. Neurochemical research 2015, 40, 1792-1798,
https://doi.org/10.1007/s11064-015-1659-1.
© 2020 by the authors. This article is an open access article distributed under the terms and conditions of the
Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).