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Isolation and in silico prediction of potential drug-like compounds from

Anethum sowa L. root extracts targeted towards cancer therapy

Article  in  Computational biology and chemistry · February 2019

DOI: 10.1016/j.compbiolchem.2018.11.025

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 Computational Biology and Chemistry 78 (2019) 242–259

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Computational Biology and Chemistry

journal homepage: www.elsevier.com/locate/cbac

Isolation and in silico prediction of potential drug-like compounds from T

Anethum sowa L. root extracts targeted towards cancer therapy
Md. Moshfekus Saleh-e-Ina,b,c, Ayan Roya, Muhammad Abdullah Al-Mansurb,
Choudhury Mahmood Hasand, Md. Matiur Rahime, Nasim Sultanab, Shamim Ahmedb,
Md. Rabiul Islamc, Johannes van Stadena,
⁎

a
Research Centre for Plant Growth and Development, School of Life Sciences, University of KwaZulu-Natal, Pietermaritzburg, Private Bag X01, Scottsville, 3209, South
Africa
b
INARS, BCSIR Laboratories, Bangladesh Council of Scientific and Industrial Research, Dhaka, 1205, Bangladesh
c
Department of Chemistry, Jahangirnagar University, Savar 1342, Dhaka, Bangladesh
d
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
e
IFST Bangladesh Council of Scientific and Industrial Research, Dhaka, 1205, Bangladesh

ARTICLE INFO ABSTRACT

Chemical compounds studied in this article: Anethum sowa L. has been used as a spice herb in the Asian and European culinary systems to add flavour and
Physcione (PubChem CID: 10639) taste. The studied plant has diverse folkloric medicinal value. Present study was designed to isolate phyto-
β-sitosterol (PubChem CID: 222284) chemicals from the hexane, chloroform and ethyl acetate extracts of the roots by various chromatographic
Stigmasterol (PubChem CID: 5280794) techniques. Based on spectral analysis (IR, LC–MS, NMR) the isolated compounds were identified as physcione
2-oxo-3-propyl-2H-chromene-7-carboxylic acid
(1), β-sitosterol (2), stigmasterol (3), 2-oxo-3-propyl-2H-chromene-7-carboxylic acid (4), bergapten (5), 3-ethyl-
(PubChem CID: not found)
7-hydroxy-2H-chromen-2-one (6) and graveolone (7). The mentioned compounds have been isolated for the first
Bergapten (PubChem CID: 2355)
3-ethyl-7-hydroxy-2H-chromen-2-one time from the roots part of the plant. Based on extensive literature review, physcione and bergapten were
(PubChem CID: 20230325) inferred to exhibit crucial bioactivities including inhibitory efficacy against various forms of cancer.
Graveolone (PubChem CID: 177751) Accordingly, in the present research approach molecular docking investigations of the isolated phytochemicals
Keywords: have been robustly executed with different oncogenes that have been reported to be actively involved in various
Anethum sowa forms of carcinoma. In silico investigations encompassing molecular docking analysis and drug-likeness profiling
Root was executed to estimate the potential therapeutic tendencies of the phytochemicals targeted towards effective
Anticancer cancer therapy. Current investigation offers meaningful know-how pertaining to potential anticancer activities
Oncogenes of the phytochemicals extracted from the roots of Anethum sowa L. and might open up new revenues towards
Molecular docking effective drug development against cancer.
Drug-likeness

1. Introduction
Anethum sowa L. (Apiaceae), is a medicinal, aromatic and spice herb
commonly known as Shulfa of Bangladesh and also found in Europe,
Asia-temperate, Africa and Asian-tropical countries. The genus
Anethum consists of four species, Anethum sowa L. (Bengali-Shulfa)
Anethum graveolens L. (Dill), Anethum foeniculoides Maire & Wilczek and
Anethum theurkauffii Maire (http://www.theplantlist.org). A. sowa and
A. graveolens, both are native to Europe and Asian subcontinent coun-
tries. The tender leaf of the A. sowa plant is used as a spice and as
flavoring agent in culinary preparations (Anonymous, 1985; Chopra
et al., 1992). The green herb, seeds and its roots are used as folkloric
medicine e.g. aromatic, carminative especially useful in flatulence, colic
and hiccups of infants and children (Woolf, 1999). Insecticidal, ovicidal
and synergistic activities of dill-apiol and essential oil of the seed part
are well known (Tomar et al., 1979). Moreover, it was reported that
seed essential oils are potential sources of antioxidants and also have
antimicrobial and antispasmodic properties (Singh et al., 2005). Pre-
vious phytochemical studies led to the isolation of dillapiol, dihy-
drobenzofuran, dihydrodillapiole, propiophenone, biphenyl derivative,
piperine alkaloid, β-sitosterol glucoside, dillapional, (4S)-(+)–carvone,
limonene and other bioactive compounds (Mehdi et al., 2007; Ahmed
et al., 1990; Walia et al., 2004; Tomar and Dureja, 2001; Jain et al.,
1986; Tomar and Mukerjee, 1981; Aggarwal et al., 2002). An extensive
literature survey pertaining to the potential bioactivities of the isolated
phytochemicals revealed a plethora of information. Inhibitory and

⁎
Corresponding author.
E-mail address: rcpgd@ukzn.ac.za (J. van Staden).

https://doi.org/10.1016/j.compbiolchem.2018.11.025
Received 19 June 2018; Received in revised form 22 October 2018; Accepted 28 November 2018
Available online 30 November 2018
1476-9271/ © 2018 Elsevier Ltd. All rights reserved.
Md. M. Saleh-e-In et al.
potential therapeutic activities against breast, liver, gastric and cervical
carcinomas have been inferred previously for the phytochemicals ber-
gapten and physcione (Fang et al., 2010; Fujioka et al., 1999; Panno
et al., 2009; Yang et al., 2003; Pan et al., 2018; Xiong et al., 2015;
Wijesekara et al., 2014). Moreover, GC–MS analysis has been found
valuable compounds and the extracts possessed good biological activ-
ities in the root part (Saleh-e-In et al., 2016, 2017) than the other parts
of this plant. In addition, the genus Anethum comprises very few spe-
cies. Therefore, we have selected the root part for the phytochemical
isolation and purification by column chromatography and characterised
by Nuclear Magnetic Resonance (NMR), Infrared (IR) and Mass Spec-
trometry (MS). In the present research endeavor, in silico molecular
docking of all isolated phytochemicals have been performed against the
conventional proto-oncogenes associated with progression of cancer.
Physicochemical and pharmacokinetic properties have also been thor-
oughly explored with a motive to assess the potential of the phyto-
chemicals to be targeted against several forms of carcinoma as pro-
mising drug-like molecules. This study is the first report on the isolation
of phytochemicals from A. sowa root extracts aided by in silico in-
vestigations to identify prospective lead/drug candidates against
cancer.
2. Materials and methods
2.1. Chemicals
n-Hexane, chloroform, ethyl acetate and methanol (Merck
Germany) were used for solvent extraction. The laboratory grade pet-
roleum ether (bp. 40–60 °C) was collected from fuel petrol by fractional
distillation. Silica gel 60 H (E Merck, 7731), silica gel 60 (0.063-
0.200 mm), anisaldehyde, sulphuric acid and acetic acid were from
Merck, Germany.
2.2. General experimental procedures
Melting points were recorded using an electro-thermal melting
point apparatus (Stuart Scientific SMP 3, UK) and OptiMelt (MPA100),
(Stanford Research Systems, USA). IR spectra were recorded using
Nicolet iS10 FT-IR Spectrometer by potassium bromide (KBr) pellets. 1H
NMR (400 MHz), 13C NMR (100 MHz) and 13C DEPT 135, 2D-NMR
spectra were recorded on a Bruker 400™ ASCEND NMR Spectrometer.
Chemical shifts are presented in δ (ppm) using tetramethylsilane (TMS)
as an internal standard and coupling constants (J) are expressed in
Hertz (Hz). LC/MS/MS was performed using a HPLC Shimadzu
Prominance UFLC Fronted system connected to a 3200 QTRAP triple
quadrupole linear iontrap MS/MS system from AB applied biosystems/
MDS Sciex (Foster City, USA). The QTrap mass spectrometer was
equipped with an integrated switching valve and a turbo ionspray
electrospray ionization (ESI) interface and used exclusively in the
multiple reaction monitoring (MRM) mode. The molecular mass (m/z)
ranges from 10 to 1700 amu. Pre-coated glass plates of silica gel
(Keiselgel 60, F254, Merck KGaA, Darmstadt, Germany) were used for
TLC analysis. Detection of spots was observed under long and short
wavelength UV light (Fisher Scientific LCF-445) at 366 and 254 nm and
on plates sprayed with anisaldehyde solution.
2.3. Plant material
The roots of A. sowa were collected from Keranigonj, near the ca-
pital city of Dhaka in Bangladesh. The plant was authenticated by Dr.
Sardar Nasir Uddin, PSO, Bangladesh National Herbarium, Dhaka,
Bangladesh. A voucher specimen with Accession Number-31,282 was
placed at the Herbarium.
243
Computational Biology and Chemistry 78 (2019) 242–259
2.4. Extraction and isolation
The plant material was air dried and ground into a powder. The root
powder (1.5 kg) was extracted successively with petroleum ether (b.p.
40–60 °C) (3 × 4 L), chloroform (3 × 2.5 L), ethyl acetate (3 × 2.5 L)
and methanol (3 × 2.5 L), at room temperature for 72 h of each. The
extracts were then concentrated in vacuo by rotary evaporator (Buchi,
R-15v) to yield 9.03 g., 5.24 g.,10.70 g. and 20.94 g of petroleum ether,
chloroform (CHCl3), ethyl acetate (EtOAc) and methanol (MeOH) ex-
tracts respectively. The extracts were triturated with petroleum ether to
get fat free extract. Petroleum ether extract (7.0 g) was achieved by
column chromatography on a silica gel (60 H) column and eluted with
Hex:DCM (95:5 to 100% DCM) and continued with increasing amounts
of MeOH in the presence of DCM (9:1 to 100% MeOH) to obtain 165
fractions (10 mL each). All fractions were collected and pooled for TLC
analysis to afford 8 groups. The second group (350 mg) was eluted with
Hex:DCM (6:4) using a silica gel column to obtain physcione 1 (2 mg).
The third group (227 mg) was fractionated with Hex:DCM (1:1 to 100%
DCM) and further purified with Hex:DCM (1:4), which resulted in the
separation of compounds 2 & 3 (9.5 mg) as a mixture of β-sitosterol and
stigmasterol. The CHCl3 extract (3.23 g) was also subjected to CC over
silica gel 60 and eluted with mixtures of Hex:EtOAc (9:1 to 100%
EtOAc) and CHCl3:MeOH (9:1 to 100% MeOH) to obtain 116 fractions
(10 mL each), which were divided into 8 groups by TLC analysis. The
third group (138 mg) was first purified with Hex:DCM (6:4 to 100%
DCM) and then DCM: EtOAc (9:1) over silica gel 60 column to obtain a
sub-fraction 19 mg. This fraction was eluted with Hex:DCM (1:4) and
10% of EtOAc in DCM which resulted in the isolation of 14.5 mg of
compound 4 (2-oxo-3-propyl-2H-chromene-7-carboxylic acid). The
fourth group (260 mg) was eluted with Hex:DCM (1:4) and DCM: EtOAc
(9:1) and yielded fractions of 82 mg and 16 mg. The fraction-1 (82 mg)
was subjected again to CC over silica gel 60 and eluted with mixtures of
Hex:DCM (1:4) furnished 40 mg of compound 5 (Bergapten). The
fraction-2 (16 mg) was subjected to further purification on a CC over
silica gel 60 with DCM: EtOAc (97:3) to obtain pure compound 6 (3-
ethyl-7-hydroxy-2H-chromen-2-one) 4 mg. The ethyl acetate extract
(9.14 g.) was subjected to VLC over silica gel 60 H with petroleum
ether, DCM, EtOAc and MeOH successively in different ratios of polarity
to obtained 27 fractions which were divided into 4 groups. The third
group of this fraction (2.10 g) was chromatographed on a silica gel and
eluted with Hex:EtOAc (95:5 to 100% EtOAc), and CHCl3: MeOH (9:1,
8:2 and 7:3) to obtain a sub-fraction (165 mg) which was further pur-
ified by CC with a mixture of DCM:EtOAc (95:5) and furnished 3.5 mg
of compound 7 (graveolone).
2.5. Characteristic data of compounds
2.5.1. Physcione (1)
Orange-yellow needle shaped crystals. mp. 199–200 °C; Rf value
0.43 (DCM:hexane, 2:3). IR(KBr): 3451, 2923, 2852, 1735,1654, 1576,
1443, 1261, 1224, 1175 cm−1. 1H NMR (CDCl3 400 MHz): δ 12.10 (1H,
s, OH), 12.30 (1H, s, OH), 7.62 (1H, s, H-4), 7.41 (1H, d, J = 2.4 Hz, H-
5), 7.07 (1H, s, H-2), 6.68 (1H, d, J = 2.8 Hz, H-7), 3.92 (3H, s, OCH3),
2.44 (3H, s, CH3). 13C NMR (CDCl3 100 MHz): δ 190.85 (C-9), 182.09
(C-10), 166.59 (C-6), 165.23 (C-8), 162.54(C-1), 148.34 (C-3),
135.30(C-5a), 133.25 (C-10a), 124.54(C-2), 121.32 (C-4), 113.72(C-
9a), 110.3 (C-8a), 108.26 (C-5), 106.81 (C-7), 56.11(OCH3), 22.18
(CH3). EI-MS(m/z) = 285.1 [M + 1]+(base peak), 256.1(5%) 254.1.
241.1, 213.1. Calculated for C16H12O5: 284.2635; found: m/z 285.1
[M + 1]+. On the basis of these spectral data, compound 1 was iden-
tified as 1,8-dihydroxy-6-methoxy-3-methylanthracene-9,10 dione
(Physcione) (Fig. 1). (Dehghan et al., 2018)
2.5.2. β-sitosterol and stigmasterol (2 & 3)
White coloured powder.mp: 151–153 °C. anisaldehyde sulphuric
acid reagent showed violet colour with Rf value: 0.54 in DCM. IR(KBr):
Md. M. Saleh-e-In et al. Computational Biology and Chemistry 78 (2019) 242–259

Fig. 1. Isolated compounds from Anethum sowa L root.

3437, 2938, 2882,1654, 1459, 1382, 1041 cm‐1. 1H NMR (CDCl3, Table 1
400 MHz): δ 3.52(1H, m, H‐3), 5.35 (1H, br, s H‐6), 5.14 (1H, m, H‐22), 1
H-NMR and 13C-NMR chemical shifts of compound 2-oxo-3-propyl-2H-chro-
5.01 (1H, m, H‐23), 1.01 (3H, s, H-19), 0.91(d, J = 6.4, 3H, H-21), 0.83 mene-7-carboxylic acid (4).
(d, J = 6.0, 3H, H-27), 0.83 (t, J = 7.6, 3H, H-29), 0.67 and 0.69 (3H, s, Atom C/H 1
H-NMR (ppm) 13
C-NMR (ppm) DEPT 135 NMR (ppm)
H-18).13CNMR (CDCl3, 100 MHz): δ 140.77 (C-5), 138.33, 33.99(C-22),
129.29, 26.13 (C-23),121.73 (C-6), 71.83 (C-3), 56.89(C-14), 55.98 (C- 2 – 162.46 C
3 – 110.16 C
17), 51.26 (C-9), 50.18, 45.87 (C-24), 42.33 (C-4, C-13), 40.50, 36.17
4 7.73 (s) 140.90 CH
(C-20), 39.71, 39.80 (C-12), 37.28 (C-1), 36.54 (C-10), 31.92 (C‐7, 8), 5 7.60 (s) 127.18 CH
31.69 (C-2), 29.18, 28.94 (C-25), 28.28 (C-16), 25.42, 23.11(C-28), 6 7.05 (s) 118.46 CH
24.38 (C-15), 21.10 (C‐11), 21.24, 18.8 (C-21), 21.24, 19.83 (C-26), 7 – 127.35 C
19.83, 19.41 (C-19), 19.02, 19.41(C-27), 12.26(C-29), 11.88, 12.05 (C- 8 5.58 (s) 114.93 CH
9 – 118.30 C
18), EI-MS (m/z) = 414.40 [M + 1]+ and 412.12 [M + 1]+ calculated 10 – 145.56 C
for C29H50O and C29H48O respectively. Ion peaks also found at m/z 11 2.43 (s) 27.77 CH2
301.2, 396.1, 297.1, 273.2, 85.2, 85.1, 55.1 (base peak). 57.2 (base 12 2.02 (s) 22.46 CH2
peak). Finally, Liebermann-burchard test produced violet blue to green 13 0.96 (s) 13.74 CH3
14 5.94 (OH) 168.24 COOH
color confirming as steroids. On the basis of these spectral data, com-
pounds 2 & 3 were identified as a mixture of β-sitosterol and stigmas-
terol (Fig. 1) (Kamboj and Saluja, 2011).
7.57 (1H, d, J = 2.4 Hz, H-2´), 7.10 (1H, s, H-8), 7.06 (1H, d,
J = 2.4 Hz, H-3´), 6.25 (1H, d, J = 9.6 Hz, H-3) and 4.25 (3H, s, OCH3);
2.5.3. 2-oxo-3-propyl-2H-chromene-7-carboxylic acid (4) 13
C-NMR (CDCl3100 MHz) δ: 161.23 (C-2), 158.38 (C-7), 152.71 (C-9),
Light yellow powder. Rf: 0.43 (DCM: EtOAc, 95:5), brown spot in 149.58 (C-5), 144.79 (C-2´), 139.2 (C-4), 112.53 (C-3), 112.53 (C-6),
anisaldehyde sulphuric acid reagent. IR (KBr): 3387 cm−1(−COOH), 106.40 (C-10), 105.04 (C-3´), 93.83 (C-8´), 60.09 (C-11, CH3). EI-MS
2961 and 2931 cm-1 υCH (aliphatic), 1744 and 1653.85 cm-1 (υC=O), m/z 217.1 (100%) [M + 1]+, 202.1, 174.1 and 156 (Fig. 1) (Intekhab
1607.42 (υC=C), 1479.42, 1288, 1105 and 696 cm−1. Calculated for and Aslam, 2008).
C13H12O4: 232.23; EI-MS m/z: 233.1 [M + 1]+. (Fig. 1) The NMR data
are shown in Table 1. 2.5.5. 3-ethyl-7-hydroxy-2H-chromen-2-one (6)
Yellow coloured powdery compound. Soluble in chloroform. Single
2.5.4. Bergapten (5) spot (Over silica gel 60 F254). UV 254 nm and anisaldehyde sulphuric
White needle shaped crystals. mp: 187–188 °C, Rf value: 0.40 acid reagent showed light gray spot. Rf value: 0.40 (DCM : EtOAc, 97:3
(DCM:Hexane, 4:1) in anisaldehyde sulphuric acid reagent showed a as mobile phase). IR (KBr): 3448.50, 2916, 2849, 1751.81, 1734.62 and
violet spot. IR (KBr): 3144, 3114, 2960, 2918, 2843, 1728, 1654, 1121, 1560 cm−1. 1H NMR (CDCl3 400 MHz): δ 6.99 (1H, d, J = 7.20 Hz, H-
1144 cm−1. 1H NMR (CDCl3 400 MHz): δ 8.13 (1H, d, J = 10 Hz, H-4), 1), 7.75 (1H, d, J = 8.4 Hz, H-5), 6.94 (1H, d, J = 2.0 Hz, H-6), 6.92

244
Md. M. Saleh-e-In et al.
(1H, d, J = 2.0 Hz, H-8), 2.42 (2H, q, H-11), 5.55 (OH, H-7), 1.24 (3H,
s, CH3); 13C-NMR (CDCl3100 MHz) δ: 161.37 (C-2), 158.1 (C-7), 145.5
(C-10), 142.00 (C-4), 127.27(C-5), 118.03 (C-6), 117.34 (C-9), 109.56
(C-3), 105.31(C-8), 22.50 (C-11), and 13.82 (C-12). Calculated for
C11H10O3 : 190.20, EI-MS m/z: 191.1 [M + 1]+ (Fig. 1) (Dzyubenko
et al., 1973).
2.5.6. Graveolone (7)
Light yellow powder, mp. 176–178 °C. Rf =0.34 (DCM) in ani-
saldehyde sulphuric acid reagent showed light brown spot. IR (KBr):
2923, 2846,1735, 1685, 1618, 1560, 1144, 745 cm−1. 1H NMR (CDCl3
400 MHz): δ 8.03 (1H, s, H-5), 7.66 (1H, d, J=9.6 Hz, H-4), 6.83 (1H, s,
H-8), 6.30 (1H, d, J=9.6 Hz, H-3), 2.76 (2H, s, H-2´), 1.56 (3H, s, H-5´),
1.48 (3H, s, H-4´). 13C NMR (CDCl3 100 MHz): δ 190.68 (C-1´), 162.40
(C-2), 159.92 (C-7), 159.29 (C-9), 143.32 (C-4), 127.38 (C-5), 117.67
(C-10), 114.62 (C-3), 113.33 (C-6), 105.63 (C-8), 80.77 (C-3´), 48.67
(C-2´), 26.72 (C-4´, C-5´). Calculated for C14H12O4: 244.24, EI-MS(m/
z) = 245 [M + 1]+, 229, 216. Compound 7 was characterized as 8, 8-
dimethyl-2H, 6H, 7H, 8H-pyrano [3,2-g]chromene-2,6-dione
(Graveolone) (Fig. 1) (Maged, 2003).
2.5.7. Literature review of the isolated compounds
An extensive literature review was carried out for the bioactivity of
the isolated compounds by electronic databases such as Scopus®,
SciFinder®, PubMed®, GoogleScholar®, The literature was searched
from the databases with no exact time limit (all fields) that relates to
the in silico studies.
2.6. Retrieval of protein and ligand structures
The isolated compounds bergapten and physcione have been pre-
viously reported to display significant anticancer activities and pro-
mising inhibitory effects in various cell lines associated with breast,
liver, gastric and cervical cancers (Table 2 and 3). Accordingly, onco-
genes associated with the respective cancer pathways have been
screened and selected as potential inhibitory targets in accordance with
previous reports (Schroeder et al., 2014; Geng et al., 2018; Becker et al.,
2006; Liang et al., 1995) for molecular docking purpose in the present
study. High resolution X-ray diffraction crystal structures of human
epidermal growth factor receptor 2 (HER2) [PDB ID: 3RCD; 3.21 Å
resolution], cyclin E [PDB ID: 5L2W; 2.80 Å resolution], tyrosine-pro-
tein kinase Met (c-Met) [PDB ID: 3CCN; 1.90 Å resolution] and B-cell
lymphoma 2 (Bcl-2) [PDB ID: 4MAN; 2.07 Å resolution] proteins were
chosen as representative oncogenes associated with breast, liver, sto-
mach and cervical cancers respectively (Schroeder et al., 2014; Geng
et al., 2018; Becker et al., 2006; Liang et al., 1995) for molecular
docking analysis with the phytochemicals isolated from the root ex-
tracts of Anethum sowa L. Respective structures were retrieved from
Protein Data Bank (PDB) (https://www.rcsb.org/). Corresponding PDB
files were amended by removing water molecules and by adding polar
hydrogen atoms and Kollman charges. AutoDock tools were used for in
the process of editing the protein structures.
The 2D structures of the phytochemicals, namely, bergapten,
physcione, graveolone and 3-Ethyl-7-hydroxy-chromen-2-one were re-
trieved from the PubChem (https://pubchem.ncbi.nlm.nih.gov/) data-
base. Furthermore, the structures of TAK-285, dinaciclib, triazolopyr-
idazine and ABT-199, the proposed inhibitors of HER2, cyclin E, c-Met
and Bcl-2 proteins respectively, were also obtained from PubChem
(Ishikawa et al., 2011; Chen et al., 2016; Parry et al., 2010; Albrecht
et al., 2008; Souers et al., 2013). The three-dimensional ligand struc-
tures, generated through Open Babel software (O’Boyle et al., 2011),
were energy minimized using PRODRG server (Schüttelkopf and van
Aalten, 2004). Gromos 96 force field was used for energy minimization.
Subsequently, Gasteiger charges were assigned employing AutoDock
Tools. Corresponding protein and ligand structures served as inputs for
molecular docking.
245
Computational Biology and Chemistry 78 (2019) 242–259
2.7. Molecular docking of the phytochemicals with the oncoproteins of
interest
Thorough information pertaining to the active site of the concerned
oncoproteins was obtained from previous reports (Ishikawa et al., 2011;
Chen et al., 2016; Albrecht et al., 2008; Souers et al., 2013). Molecular
docking of the phytochemicals at the active site of the proteins was
achieved employing a grid-based docking protocol opting a rigid pro-
tein receptor and flexible ligand docking approach in AutoDock Vina
(Trott and Olson, 2010). Grid boxes [each with coordinates of 30, 30
and 30 in x, y and z dimensions] encompassing the active site residues
of the concerned receptor proteins were set for the docking purpose.
Docking results of AutoDock Vina were further validated employing
DINC server (Antunes et al., 2017). The docked conformations with
lowest binding energies and RMSD scores < 2.0 Å were chosen for
further interaction profiling. Interactions between the receptor proteins
and the concerned phytochemicals of interest were minutely analysed
using PyMol (version 1.7.4) software package and the Protein-Ligand
Interaction Profiler (PLIP) server (Salentin et al., 2015).
2.8. Assessment of physicochemical features, pharmacokinetic properties
and evaluation of potential toxicity of the phytochemicals
Methodical assessment of the physicochemical features and phar-
macokinetic properties of the phytochemicals were executed with a
motive of exploring their drug-like potential. Physicochemical proper-
ties of the compounds and their accordance with the general rules of
drug-likeness viz., Lipinski’s rule of Five (RO5), Veber’s rule, GSK 4/400
rule and Pfizer 3/75 rule were assessed using SwissADME and FAF-
Drugs4 servers (Daina et al., 2017; Lagorce et al., 2017a,b).
Human intestinal absorption (HIA) was estimated using the pkCSM
server (Pires et al., 2015) and revalidated by admetSAR server (Cheng
et al., 2012). Features like oral bioavailability and solubility were es-
timated employing FAF-Drugs4 server and pertaining results were
correlated with predictions from SwissADME.
Assessment of toxicity of a potential therapeutic molecule is one of
the most crucial aspects in effective drug development. Thorough in
silico estimation pertaining to the toxicity parameters of the concerned
phytochemicals involving carcinogenicity, mutagenicity and tumor-
igenicity was executed by comparing the prediction results of multiple
software packages and web-based tools. In the present study, a con-
cerned compound predicted to display potential toxicity by any one of
the servers or software has been inferred to be potentially toxic. Such a
stringent scheme has been opted to abate the probabilities of proposing
phytochemicals with potential toxic adversities. Potential carcinogeni-
city was assessed employing admetSAR server and ToxTree v4.6.13
software (Patlewicz et al., 2008). Pan-Assay Interference Structures
(PAINS) medicinal chemistry estimation was achieved with SwissADME
and FAF-Drugs4 servers. Potential mutagenic effects of the phyto-
chemicals were investigated through ProTox-II (Banerjee et al., 2018)
and admetSAR servers. Probable tumorigenic and irritation effects of
the compounds were assessed using Osiris Data Warrior (Sander et al.,
2009) and ToxTree v4.6.13 software packages.
3. Results and discussion
3.1. Characterization of compound
The IR spectrum of compound 4 showed the broad band at 3350-
3000 cm−1 which is assigned to −COOH group and the bands at 2961
and 2931 cm-1 are due to υCH (aliphatic). The IR bands at 1744 and
1653.85 cm-1 are assigned to υC=O of lactone and −COOH group re-
spectively whereas, the band at 1607.42 is due to υC=C (benzene ring).
The other important bands appeared at 1479.42, 1288, 1105 and
696 cm−1. The 1H-NMR spectrum showed (Table 1) the broad signal at
δH 0.958 having 9H of CH3 group, broad signal at δH 1.4–1.6 with 6H
 Table 2
Reported biological activities of the isolated compounds and occurrence in different plant species.
Plant species and parts References Bio-activities Organism/Cell line/Reference standard References

Bergaptene
Glehnia littoralis, root Fang et al. (2010) Anticancer Liver cancer cell line HEP-G2 Fang et al. (2010)
Anticancer Stomach cancer cell line SGC-7901 Fang et al. (2010)
Md. M. Saleh-e-In et al.

Citrus aurantium L., fruit Juice Malhotra et al. (2001) Inhibit cytochrome P450 3A4 enzymes – Malhotra et al. (2001)
Peucedanum japonicum, root Huong et al. (1999) Monoamine oxidase Monoamine oxidase enzyme Huong et al. (1999)
Angelica japonica, root Fujioka et al. (1999) Antiproliferative Human gastric adenocarcinoma Fujioka et al. (1999)
MK-1 cell
Anticholinesterase activity Acetylcholinesterase (AChE) enzyme Orhan et al. (2008)
Anticancer Breast cancer cells MCF-7 Panno et al. (2009)
Cnidium monnieri, fruits Basnet et al. (2001) Anti-itching activities Mice Basnet et al. (2001)
Ferulago trifida Boiss, fruits Lu et al. (2015) Lipid lowering activity Swiss Albino mice and Adult male Charles Foster rats Lu et al. (2015)
Antimycobacterial Mycobacterium tuberculosis H37Rv Chiang et al. (2010)
Heracleum persicum, roots Dehghan et al. (2017) α-Glucosidase inhibitory and antioxidant activity α-glucosidase and its 2,2-diphenyl- Dehghan et al. (2017)
1-picrylhydrazyl radical
Angelica dahurica, roots Li and Wu (2017) Anti-allergic inflammation RBL-2H3 cells Li and Wu (2017)
(TNF-α, IL-1β and IL-4)
Euodia daniellii Yoo et al. (2002) Cyclooxygenase-2 inhibitory activity Cyclooxygenase enzyme Yoo et al. (2002)
Angelica officinalis L. fruits Senol et al. (2011) Anti-cholinesterase (AChE and BChE) activity Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme Senol et al. (2011)
Ficus religiosa L., bark Singh et al. (2014) GABA (gamma-aminobutyric acid) aminotransferase Swiss Albino mice brain Singh et al. (2014)
inhibitory activity
Ferulago bracteata, roots Karakaya et al. (2018) α-amylase and α-glucosidase inhibitory activities α-amylase and α-Glucosidase Karakaya et al. (2018)
Ficus hirta, roots Yang et al. (2018a) Anti-inflammatory and proresolution activities Zebrafish larvae Yang et al. (2018a)
Cytotoxic A2780RCIS (MRP2 overexpressing human epithelial ovarian cancer Mirzaei et al. (2017)
cell line), EPG85.257RDB (MDR1 overexpressing human gastric
adenocarcinoma
cell line), MCF7MX (BCRP overexpressing human epithelial

246
breast cancer cell line), A2780,
EPG85.257 and MCF7 cells.
Heracleum mantegazzianum Sommier & Walasek et al. (2015) Antimicrobial Gram-positive, Gram-negative and Yeasts Walasek et al. (2015)
Levier, fruits
Treculia obovoidea, twigs Kuete et al. (2007) Antimicrobial activity Gram-positive, Gram-negative and Yeasts Kuete et al. (2007)
Anti-inflammatory (lipopolysaccharide-induced RAW264.7 cells Zhou et al. (2017)
inflammation)
Zanthoxylum flavum Vahl, roots. Ross et al. (2008) Antimalarial Plasmodium falciparum Ross et al. (2008)
CYP1A1-enzyme inhibition activity α-naphthoflavone Joshi et al. (2018)
Ruta graveolens Diwan and Malpathak topoisomerase I inhibitors Calf thymus topoisomerase I Diwan and Malpathak
(2009) (2009)
Ferulago carduchorum, aerial parts Golfakhrabadi et al. Antimicrobial and acetylcholinesterase inhibitory Organism: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Golfakhrabadi et al.
(2016) activities Candida albicans, (2016)
Enzyme: acetylcholinesterase
Angelica shikokiana, Mira and Shimizu Cytotoxicity (tubulin polymerization and histone Human hepatocellular carcinoma, rhabdomyosarcoma (RD), colorectal Mira and Shimizu (2015)
aerial parts (2015) deacetylase 8 (HDAC8) carcinoma, human epithelioma and human breast adenocarcinoma,
human lung fibroblasts
Radix Angelicae pubescentis, Yang et al. (2015a) Blood-Brain Barrier Permeability MDCK-pHaMDR cell Yang et al. (2015a)
Chinese medicine
Xanthotoxin-metabolic activity of CYP6B1 CYP6B1 Protein Wen et al. (2006)
Antifungal S. sclerotiorum, T. cucumeris, B. cinerea, F. graminearum, C. capsici, Song et al. (2017)
Trachyspermum roxburghianum (DC.) Craib H Wisetsai et al. (2018) Cytotoxic Human small cell lung cancer (NCI-H187) Wisetsai et al. (2018)
Inhibitory effects on diabetes-related osteoporosis wild-type male mice Li et al. (2016)
Angelica polymorpha, stem Kwon et al. (2017) Anti-cholinesterase Acetylcholinesterase Kwon et al. (2017)
Heracleum dissectum, roots Zhang et al. (2017) Anti-Inflammatory RAW264.7 cells Zhang et al. (2017)
Angelica archangelica L. Rajtar et al. (2017) Cytotoxic and anti-viral Vero cell, HSV-1, CVB3 Rajtar et al. (2017).
Anticancer Human breast cancer MCF7 and ZR75-1 (ZR75) cells Santoro et al. (2016)
Pleurospermum amabile Wangchuk et al. (2016) Anti-helminths (anthelmintic activity) Schistosoma mansoni, Trichuris muris Wangchuk et al. (2016)
Anti-resorptive effect Bone marrow stromal Xiao et al. (2015)
cells (BMSCs)
Computational Biology and Chemistry 78 (2019) 242–259

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 Table 2 (continued)

Plant species and parts References Bio-activities Organism/Cell line/Reference standard References

Foeniculum vulgare Yang et al. (2015b) Anti-inflammatory and antioxidant RAW 264.7 cells Yang et al. (2015b)
Angelica keiskei Koidzumi Protein tyrosine phosphatase Oleanolic acid Li et al. (2015)
1B (PTP1B) inhibitory activity
Clausena anisata (Will.) Hook, leaves and Tatsimo et al. (2015) Antimicrobial Vibrio cholerae strains: NB2, SG24, CO6 and PC2. Shigella flexneri 2a and Tatsimo et al. (2015)
Md. M. Saleh-e-In et al.

stem bark Staphylococcus aureus ATCC 25,923.

Angelica species, roots & seeds
Cnidium species, fruits
Ligusticum officinale Koch, roots
Zanthoxylum schinifolium,
Angelica archangelica L.,
roots and fruits
Ficus carica L.,
milky sap from leaves stem
Angelica gigas, stem
Citrus bergamia, fruits
Ruta graveolens L.,
fruits, shoots and roots
Angelica glauca Edgew, roots
Heracleum crenatifolium, fruits
Cnidium monnieri, fruits
Cnidium monnier, fruits
Sumiyoshi et al. (2014) Anti-tumor effects B16F10 melanoma cells Sumiyoshi et al. (2014)
Guzman et al. (2013) Antimycobacterials Mycobacterium smegmatis, Mycobacterium bovis, RAW 264.7 murine Guzman et al. (2013)
macrophage cells
Choi et al. (2012) Antibacterial Activity E. coli, S. aureus and Helicobacter pylori strains 26695 Choi et al., (2012)
Wszelaki et al. (2011) Anti-cholinesterase Acetylcholinesterase and butyrylcholinesterase Wszelaki et al. (2011)
Chung et al. (2011) Immunotoxicity activity Aedes aegypti Chung et al. (2011)
Park et al. (2011) Aldose reductase activity Rat lens aldose reductase from Sprague-Dawley rats Park et al. (2011)
Borgatti et al. (2011) Anti-inflammatory (Cystic fibrosis) IB3-1 cells and CuFi-1 cell Borgatti et al. (2011)
Diwan and Malpathak Topoisomerase I inhibitors Calf thymus topoisomerase I Diwan and Malpathak
(2009) (2009)
Photoactivation, enhancement of p53 gene expression, and MCF-7 and SKBR-3 breast cancer cells Panno et al. (2009)
induces apoptosis in human breast cancer cells
Bergaptol O-methyltransferase (BMT) activity White calli of Glehnia littoralis Ishikawa et al. (2009)
Saeed and Sabir (2008) Irritant and cytotoxic activity Albino mice, Brine Shrimp Saeed and Sabir (2008)
Tosun et al. (2008) Anticonvulsant activity Male albino mice Tosun et al. (2008)
Zhang et al. (2007) Antiosteoporotic activity Wister rat Zhang et al. (2007)
(osteoblastic and marrow cells).
Yang et al. (2003) Cytotoxic activity Leukemia cells (HL-60, HeLa, Yang et al. (2003)
CoLo 205, P-388)

247
Peucedanum zenkeri, Ngwendson et al. (2003) Antimicrobial Cryptococcus neoformans ATCC 90113, Mycobacterium intracellulare ATCC Ngwendson et al. (2003)
23,068.
Aquilaria agallocha Huong et al. (2002) Monoamine oxidase inhibitors Monoamine oxidase enzyme Huong et al. (2002)
Inhibition of CYP 3A4 activity in human liver microsomes Human liver Ho et al. (2001)
Angelica pubescens, roots Chen et al. (1995) Anti-Inflammatory and analgesic activities Male ICR mice Chen et al. (1995)
Physcione/Parietin
Rheum turkestanicum, roots Dehghan et al. (2018) Antioxidant, α-amylase, α-amylase and Dehghan et al. (2018)
α-glucosidase α-glucosidase, DPPH radical
Ventilago denticulata Molee et al. (2018) Cytotoxic, Hep G2 Molee et al. (2018)
Hepatocellular carcinoma (HCC) Human HCC cell lines Huh7 and Bel7402 Pan et al. (2018)
6-phosphogluconate dehydrogenase (6PGD) inhibition of in Cancer cells (MDA-MB-468, MCF-7, SkBr-3 and MDA-MB-231), normal Yang et al. (2018b)
breast cell (MCF-10 A and HMT-3522).
cancer.
Yin-Chen-Hao Tang (YCHT) Chinese Xiang et al. (2016) Inhibit severe acute pancreatitis Sprague-Dawley (SD) rats Xiang et al. (2016)
medicine progress.
(Artemisiacapillaris Thunb.,
Gardeniajasminoides Ellis., and
Rheumofficinale Baill,
2: 1: 1)
Morinda citrifolia, fruits Joy et al. (2016) Antiosteoporotic activity Rats Joy et al. (2016)
Polygonum multiflorum, roots Yoon et al. (2016) Human sialyltransferases gene expression effects Human neuroblastoma SK-N-BE(2)-C cells Yoon et al. (2016)
Rumex abyssinicus, roots Tala et al. (2018) Zoosporicidal activity Late blight pathogen Phytophthora capsici Tala et al. (2018)
Acute lymphoblastic leukemia (ALL) Human pre-B ALL cell lines NALM6 and SUPB15 Gao et al. (2017)
Rheum tanguticum Maxim. Ex Balf. rhizomes Pham et al. (2017) Antimicrobial Pathogenic bacterial strains Pham et al. (2017)
Cassia obtusifolia, seeds Jung et al. (2017) Protein tyrosine phosphatase 1B and PTP1B (human recombinant), Jung et al. (2017)
α-glucosidase inhibitory activities α-glucosidase
Eurotium cristatum, fungi Yan et al. (2017) Immunization effect T cells Yan et al. (2017)
Polygonum cuspidatum, roots Khalil et al., (2016) Anti-Helicobacter pylori Helicobacter pylori 43,504 strain Khalil et al. (2016)
Anti-tumor action. Nasopharyngeal carcinoma cell line CNE2 Pang et al. (2016)
(human nasopharyngeal carcinoma)
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 Table 2 (continued)

Plant species and parts References Bio-activities Organism/Cell line/Reference standard References

Teloschistes flavicans (Sw.) Norm., lichen Comini et al. (2017) Photodynamic antibacterial effects and cytotoxic activity Gram positive Comini et al. (2017)
bacteria (Staphylococcus aureus ATCC 29,213 and Staphylococcus
epidermidis ATCC 12,228) and two Gram negative bacteria
Md. M. Saleh-e-In et al.

(Escherichia coli ATCC 25,922 and Pseudomonas aeruginosa

ATCC 27,853), Vero cell line 76
ATCC CRL-587
Rheum palmatum, root Jiang et al. (2016) Human CYP and SULT enzymes inhibition Human CYP and SULT enzymes Jiang et al. (2016)
Cassia obtusifolia, seeds Jung et al. (2016) β-secretase and cholinesterase Acetylcholinesterase and butyrylcholinesterase, Jung et al. (2016)
β-site amyloid precursor protein (APP) cleaving enzyme 1
Anticancer effects (6-phosphogluconate dehydrogenase) K562, HEL, KG1a Elf et al. (2017)
(6PGD) inhibition
Inhibition of human colorectal cancer Cancer cells (SW620) Han et al. (2015)
Ichthyotoxicity Zebrafish embryo Bai et al. (2016)
Anti-proliferative effect Human Gastric adenocarcinoma SGC-7901 cell Xiong et al. (2015)
Xanthoria parietina, Lichen Basile et al. (2015) Antiproliferative, antibacterial and antifungal Gram-positive, Gram-negative, fungi, MCF-7 and MDA-MB231 cell lines Basile et al. (2015)
Rheum emodi, rhizomes Tripathi et al. (2014) Nematicidal activity Meloidogyne incognita Tripathi et al. (2014)
(Root-knot nematode)
Penicillium herquei, fungus Tansakul et al. (2014) Cytotoxic, antibacterial, antioxidant KB, MCF-7 and Tansakul et al. (2014)
noncancerous Vero cell lines, antibacterial activity against standard S.
aureus ATCC25923 and methicillin-resistant
S. aureus SK1, DPPH
Eurotium herbariorum NU-2 from Karebushi Miyake et al. (2014) Anti-oxidant DPPH-radical Miyake et al. (2014)
Aspergillus wentii EN-48, alga-derived fungus Li et al. (2014) Anti-oxidant DPPH-radical Li et al. (2014)
Eurotium tonpholium Awaad et al. (2014) Anti-leishmanial activities Leishmania major Awaad et al. (2014)
Rhubarb rhizome Choi et al. (2013) Anti-inflammatory RAW264.7 murine macrophages, Caco-2 cell line (ATCC #HTB-37) Choi et al. (2013)
(P-glycoprotein function and expression)

248
Rheum rhabarbarum Hu et al. (2014) Anti-inflammatory RAW264.7 cells Hu et al. (2014)
(lipopolysaccharide)
Polygonum multiflorum Wang et al. (2014) Lipid regulation activity Steatosis hepatic L02 cell, Wang et al. (2014)
(total cholesterol and triglyceride)
Microsporum sp. (fungus) from red alga Wijesekara et al. (2014) Cytotoxic effect HeLa cells Wijesekara et al. (2014)
Lomentaria catenata (human cervical cancer)
Cyrtomium fortumei (J.) Smith, rhizomes Yang et al. (2013) Antitumor activities Stomach cancer cell (MGC-803), prostate cancer cell (PC3), malignant Yang et al. (2013)
melanoma cell (A375), Mouse fibroblast cell (NIH3T3).
Psorospermum aurantiacum, leaves Tchakam et al. (2012) Antimicrobial and antioxidant activities Bacteria and fungal strains, DPPH radical Tchakam et al. (2012)
Cassia siamea, roots Kumar et al. (2013) Antiobesity Pnitrophenyl palmitate (PNPP) Kumar et al. (2013)
(Pancreatic lipase inhibition)
Active against craniocerebral injury (superoxidase Male Sprague-Dawley rats Wang et al. (2012)
dismutase)
Xanthoria parietina, lichen Backorova et al., 2012 Anticancer Cell lines A2780 (human ovarian carcinoma) and HT-29 (human colon Backorova et al. (2012)
adenocarcinoma)
Tripterygium hypoglaucum, roots Wei et al. (2011) Antitumor activity The ovarian cancer A2780 and OVCAR-3 cell lines (ATCC), normal cell Wei et al. (2011)
(IOSE144).
Morinda officinalis, roots Wu et al. (2009) Antiosteoporotic activity Primary osteoblastic cells (1 × 108/L) and bone marrow cells Wu et al. (2009)
Berchemia floribunda (WALL.) Brongn., roots Wei et al. (2008) Hepatoprotective activity (D-galactosamine-induced Rat hepatic epithelial WB-F344 cells Wei et al. (2008)
toxicity)
Rheum palmatum, roots Lin et al. (2008) Liver fibrosis (profibrogenic HSC-T6 cells Lin et al. (2008)
action of TGF-β1 via HSC chemotaxis and ECM production
Reynoutria sachalinensis Na et al. (2008) Type-2 diabetes and obesity (Protein Tyrosine Phosphatase PTP1B (human, recombinant) enzyme Na et al. (2008)
1B inhibitory Activity)
Polygonum cuspidatum Leu et al. (2008) Antityrosinase activity Mushroom, tyrosinase and Leu et al. (2008)
L-DOPA
Polygonum multiflorum Thunb., roots Choi et al. (2007) Cdc25B phosphatase inhibitors Escherichia coli strain BL21 for glutathione transferase (GST) and Cdc25B Choi et al. (2007)
proteins
Rhubarb rhizome Ngoc et al. (2008) Lipoxygenase inhibitory Soybean lipoxygenase Ngoc et al. (2008)
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Md. M. Saleh-e-In et al. Computational Biology and Chemistry 78 (2019) 242–259

and broad singlet at δH 2.03 for 2H. Moreover, a broad doublet found at

Arvindekar et al. (2015)

δH 2.4 (6 H) for the aliphatic region. There are two broad singlets found

Panigrahi et al. (2015)

Demirezer and Rapid
Kouam et al. (2006)
at δH 5.58 and 5.84 corresponding to 2H and 1H respectively in the
El-Halawany et al.

Zhou et al. (2006)

Kuo et al. (2001)
Xu et al. (2006) olefinic region. The signal at 5.84 might be due to an olefinic group. In

Li et al. (2005)
the aromatic region, there are three broad signals at δH 7.05, 7.60 and
References

7.73. The 13C-NMR spectrum showed (Table 1) 5 signals in the aliphatic

(2007)

(1997)
region which appeared at δ 13.80 (CH3), 22.46 (2×CH2), 22.79 (CH2),
27.80 (2×CH2) and 27.96 (CH2). There are 15 signals which appeared
over δ 100 ppm at δ 105.47, 109.39, 110.16, 114.93, 116.47, 117.98,
118.30, 118.46, 127.18, 127.35, 140.90, 142.42, 145.56, 162.46,
168.24. The DEPT-135 spectrum (Table 1) showed one CH3 group, four
negative signals at CH2 position and 8 CH carbons. The rest of the
signals (missing in DEPT-135) at 140.90, 142.42, 145.96, 162.46 and
Male Wistar albino rats and alpha glucosidase enzymes 168.24 are quaternary carbon atoms. Among these, the carbon signals
at δ 168.24 and 162.46 are definitely carbonyl carbon (C]O) of COOH
Human mesangial cells from human kidney tissues

and lactone respectively. The 1H, 1H COSY-NMR spectrum of 4 showed

(Supplementary Fig. S17) a correlation between CH2 and CH3 group as
Rat primary hepatocytes and HepG2 cells

coupling position. This is obtained by joining the cross peaks (A, C) and
Organism/Cell line/Reference standard

diagonal peaks (B, D). Another correlation between two CH2 groups is
obtained by joining EF and GH which form rectangle. The correlation is
seen by the formation of a rectangle by joining the I, K cross peaks and
pBR 322 plasmid DNA, cells

J, L diagonal peaks. This correlation is another ring forming AB system

(HT-29, MCF-7, HepG-2)

Cancer cell (A431, PC3)

having 2 doublets. There are some additional peaks which indicates

Phytopthora infestans
Fusarium oxysporum

that this fraction is a mixture containing some olefinic protons at δH

Gibberella zaeae
PTP1B enzyme

5.58 and 5.84. The DBE ([2 × 13 + 2)-12]/2 = 8) of C13H12O4 calcu-

α-glucosidase

Brine Shrimp

lated as 8. On the basis of spectral data, the probable assignment of this

MCF-7 cell

compound is 2-oxo-3-propyl-2H-chromene-7-carboxylic acid

(C13H12O4). In the present study, rest of the isolated compounds are
reported in various species of the different parts of the plant, Hence, all
these compounds were isolated for the first from the roots of A. sowa.
Human protein tyrosine phosphatase 1B (hPTP1B) activity

(extracellular signal-regulated kinase) phosphorylation,

DNA topoisomerase I and II inhibitory activities and

3.2. Survey of bioactivities of the isolated compounds

Protein kinase inhibitors (inhibition against ERK

Based on a comprehensive literature survey on the isolated com-

Inhibit human mesangial cells proliferation

pounds of A. sowa roots, physcione (1) and bergapten (5) have been
Estrogenic and anti-estrogenic activities

reported to display diverse pharmacological activities (Table 2) of im-

Anti-diabetic and alpha glucosidase

mense significance. This survey includes an overview of the anti-cho-

(Type-II diabetes and obesity)

linesterase, anticancer, anti-microbial, anti-inflammatory, anti-oxidant

and anti-diabetic activities. Among the reported activities, anti-cancer
α-glucosidase inhibitory

and anti-tumour behavior on various cell lines has been well stated and
established by previous researchers. On the other hand, reported data
antifungal activity

inhibitory action

for the rest of isolated compounds are scarce pertaining to different

Bio-activities

Cytotoxicity

Cytotoxicity
cytotoxicity

biological activities. On the basis of different in vivo and in vitro

bioactivities, limited reports have been published on molecular inter-
action studies against specific target proteins and have been compared
with reference drug molecules (Table 3). Present survey provides en-
ormous information about the bioactivities of the isolated phytochem-
Arvindekar et al. (2015)

Panigrahi et al. (2015)

Demirezer and Rapid

icals among which anticancer potential appeared to be the most pro-

Kouam et al. (2006)
El-Halawany et al.

Zhou et al. (2006)

Kuo et al. (2001)

minent attribute. However, in silico investigations regarding molecular

Xu et al. (2006)

Li et al. (2005)

interactions of the phytoconstituents with specific oncogenes, involved

References

in progression of various forms of carcinoma, has not yet been exe-

(2007)

(1997)

cuted. Present research has been targeted towards the elucidation of

reported anticancer activities of the isolated compounds from the per-
spective of in silico molecular interaction profiling with target onco-
genes of interest. Subsequent assessment of physicochemical and
Harungana madagascariensis, stem bark
Ardisia japonica (Thunb.), whole plant

pharmacokinetic properties of the phytoconstituents has also been ex-

Polygonum hypoleucum Ohwi, stems

tensively executed.

3.3. In silico investigation of molecular interactions

Cassia occidentalis, seeds
Rheum emodi, rhizomes
Plant species and parts

Polygonum multiflorum

Rumex scutatus, roots

Table 2 (continued)

Potential bioactivities of the concerned phytochemicals have been

Thunb., roots
Cassia tora, seeds

elaborately enlisted in Tables 2 and 3 after extensive literature survey.

All the phytochemicals with reported bioactivities were found to dis-
play significant anticancer activities in general. Accordingly, in this
Rhubarb

present work we have focused on the potential anticancer properties of

the concerned phytochemicals. Interestingly, bergapten and physcione

249
 Md. M. Saleh-e-In et al.

Table 3
Reported In-Silico studies of the isolated compounds from Anethum sowa L. roots.
Analogue compounds/ Activities Bind protein molecule Binding energy (kcal/mol) References
Reference compounds (Compound/Analogue)

Bergaptene
Rifampicin Mycobacterium tuberculosis (MBT) Mycobacterium dependent RNA polymerase −58.23/−68.6 Kapoor et al. (2013)
required for RNA synthesis
Isoniazid Mycobacterium tuberculosis (MBT) Enoyl-acyl carrier protein (InhA) −74.91/−74.49 Kapoor et al. (2013)
– Anti-Vitiligo Photoallergen complex – da Silva et al. (2009)
– Anti-Oral cancer HER2 (human epidermal growth factor 2) −79.54 Kumar et al. (2016)
Anti-gastric ulcer Histamine H2 receptors −24.886 Chaudhary et al. (2017)
Anti-cholinesterase huBChE −7.9 Senol et al. (2011)
Insect cytochrome P450 monooxygenase inhibition CYP6B1 protein −48.1 Baudry et al. (2003)
Vinblastine and Cytotoxicity (tubulin polymerization and histone Tubulin protein and HDAC8 Tubulin: −52.03 and −70.96 (vinblastine and Mira and Shimizu (2015)
colchicine deacetylase 8 (HDAC8) inhibitory activity) colchicine), histone deacetylase 8 : −83.39
Anti-virus activity Virus proteins: Junin, Hanta, Junin(−74.5465), Hanta (−77.867), Dengue Badoni et al., (2015)
Dengue, Marburg, Ebola (−78.2697), Marburg (−62.0788), Ebola (−65.5887)

250
Tazobactam Inhibitory activity against New Delhi Metallobeta- New Delhi Metallo-beta-lactamase-1 −200.55/−241.4 Thakur et al., (2014)
lactamase harboring Escherichia coli,
Estrogenic activity Human estrogen receptor α and β (ERα and ERβ) ERα :−71.2, ERβ − 77.6 Powers and Setzer (2015)
Physcione/Parietin
AChE inhibition Mouse amyloid beta peptide (Aβ)1–42 (amyloid precursor protein) – Cai et al. (2018)
Cassia occidentalis (CO) seeds toxicity in blood Serum albumin protein −6.97 (AUTODOCK 4.2), −4.73(CDOCKER (Accelrys Panigrahi et al. (2015)
Discovery Studio)
Antimicrobial activity PBP1a (Acinetobacter baumannii), Alr (Escherichia coli), IARS and Ddl – Alves et al. (2014)
(Thermus thermophiles), DNA gyrase subunit B and DHFR
(Staphylococcus
Aureus), Topo IV and DHPS (Streptococcus pneumonia).
Inhibition of adrenergic receptor Human β2-adrenergic receptor – Feng et al. (2013)
Pregnane X receptor activity PXR on hepatic cells Human pregnane X receptor (PXR). CDOCKER interaction Liu et al. (2011)
energy (CIE) (29.92)
Hypericins and Thioredoxin reductase activity Cytosolic (TrxR1) and – Sorrentino et al. (2011)
mitochondrial (TrxR2) thioredoxin
Tau Protein Inhibitionr Tau VQIVYK segment complexed with orange-G Cornejo et al. (2016)
Computational Biology and Chemistry 78 (2019) 242–259
Md. M. Saleh-e-In et al.
Fig. 2. Flowchart displaying the pipeline of molecular interaction analysis and binding scores of the isolated phytoconstituents with respective oncogenes.
have been reported to biologically inhibit specific cancers associated
with breast, liver, gastric and cervix (Table 3). In the present work,
extensive molecular docking analyses of the concerned phytochemicals
with oncogenes associated with different cancer pathways have been
executed. Proto-oncogenes are group of genes, associated with normal
cell growth and division, which on encountering a mutation or a series
of mutations lead to carcinoma (Weinstein and Joe, 2006). The mutated
gene leading to uncontrolled cell growth and proliferation and ab-
normal cell death leads to cancer progression and has been defined as
an oncogene (Weinstein and Joe, 2006; Adamson, 1987). Human epi-
dermal growth factor receptor 2 (HER2), a member of the erbB class of
tyrosine kinase receptors, is expressed at cell surface and is associated
with crucial biological processes such as cell growth and differentiation
(Schroeder et al., 2014). Overexpression of HER2 has been reported to
be associated with breast cancer progression (Slamon et al., 1989;
Bacus et al., 1994). Association of HER2 in breast carcinoma has es-
tablished the oncogene as an automatic therapeutic target for inhibition
to combat cancer (Schroeder et al., 2014). Cyclin E (cyclins E1 and E2)
proteins are imperative constituents of the cell cycle orchestra and
crucially regulate cell differentiation (Geng et al., 2018). Over-
expression of cyclin E leads to uncontrolled cell proliferation and ab-
normal apoptosis (Jung et al., 2001). Liver cancer has been character-
ized by overexpression of cyclin E. Accordingly, cyclin E has been
considered as a potent therapeutic target of immense gravity (Weinstein
and Joe, 2006) c-Met, a receptor tyrosine kinase, has been reported to
be crucially involved in the progression of gastric carcinoma (Morishita
et al., 2014). c-Met binds with its ligand hepatocyte growth factor and
regulates an array of cellular signaling pathways associated with cell
proliferation, differentiation and migration (Ma et al., 2003; Organ and
Tsao, 2011). Abnormal expression and mutation events in c-Met have
been reported to be involved in the development and advancement of
gastric cancer (Becker et al., 2006). c-Met oncogene has been suggested
to be a potential target of inhibition in the domain of drug development
against gastric cancer (Kim et al., 2018; Becker et al., 2006). B-cell
251
Computational Biology and Chemistry 78 (2019) 242–259
lymphoma 2 (Bcl-2) family proteins are considered to be oncoproteins
that inhibit apoptosis and programmed cell death (Bodur and Basaga,
2012). Bcl-2 has been observed to be associated critically in the de-
velopment of cervical cancer by influencing the permeability transition
pore of mitochondrial membrane and thus, considered as suitable target
for drug design against cervical carcinoma (Munakata et al., 2005;
Bodur and Basaga, 2012).
In-depth interaction profiling of the phytochemicals with the on-
cogenes for breast, liver, gastric and cervical carcinomas was performed
and was subsequently compared with the binding patterns of the pro-
posed oncogene inhibitors. The pipeline employed and respective
binding (docking) scores have been detailed in Fig. 2. Detailed in-
formation pertaining to the active site residues of the concerned on-
coproteins interacting with the phytochemicals (isolated from the root
extracts of A. Sowa) and the inhibitors have been provided in Table 4.
The best binding conformations of the phytoconstituents displaying
highest binding affinities with the respective oncoproteins associated
with breast, liver, gastric and cervical carcinomas have been depicted in
Figs. 3–6.
HER2, associated with breast cancer, was found to display highest
binding affinity of -8.4 kcal/mol with graveolone (Fig. 3) followed by
physcione (-8.3 kcal/mol), 3-Ethyl-7-hydroxy-chromen-2-one
(-7.1 kcal/mol) and bergapten (-7.0 kcal/mol) (Table 4). HER2 inhibitor
TAK-285 was found to efficiently bind at the ATP-binding pocket
(Ishikawa et al., 2011) and exhibited a high binding score of -10.3 kcal/
mol. It was well evident from extensive analysis that all the phyto-
chemicals interacted well at the active site of the HER2 protein
(Table 4).
Cyclin E, associated with liver cancer revealed a high binding affi-
nity (-10.2 kcal/mol) with physcione (Fig. 4 and Table 4) which was
found close to the binding score of the oncoprotein with its inhibitor
dinaciclib (-10.3 kcal/mol) bound at the ATP binding pocket (Chen
et al., 2016). Graveolone, bergapten and 3-Ethyl-7-hydroxy-chromen-2-
one also displayed decent binding affinities of -8.8 kcal/mol, -8.3 kcal/
 Md. M. Saleh-e-In et al.

Table 4
Detailed interaction profile of the phytochemicals and inhibitors with the oncoproteins of interest.
Oncoprotein Compounds Inhibitor

Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2-one TAK-285

HER2 Average Binding −7.0 ± 0.05 −8.3 ± 0.03 −8.4 ± 0.03 −7.1 ± 0.02 −10.3 ± 0.05
Energy (kcal/mol)
Interacting residues Leu 726, Val 734, Ala 751, Leu Leu 726, Val 734, Ala 751, Thr 798, Leu Val 734, Thr 862, Phe Leu 726, Val 734, Thr 798, Leu 800, Leu Ala 751, Lys 753, Leu 785, Leu 800, Met 801, Leu 852,
852, Met 801, Thr 862 800, Met 801, Leu 852, Gly 804, Cys 805 1004, Ser 783 852, Met 801, Thr 862, Asp 863 Thr 862, Phe 1004, Phe 864*, Leu 796**, Thr 798**

Oncoprotein Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2-one Dinaciclib

Cyclin E Average Binding Energy −8.3 ± 0.05 −10.2 ± 0.04 −8.8 ± 0.04 −8.2 ± 0.03 −10.3 ± 0.03
(kcal/mol)
Interacting residues Asp 108, Leu 134, Phe 150, Phe Leu 134, Ala 146, Arg 143 Phe 101, Asp 108, Phe 109, Glu 133, Phe 82, Phe 109, Met 112, Leu 134, Glu Ile 10, Val 18, Ala 31, Phe 80, Phe 82, Leu 134, Leu 83,
101* Leu 134 149, Phe 101* Lys 89, Asp 145

252
Oncoprotein Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2-one Triazolopyridazine

c-Met Average Binding Energy (kcal/ −7.9 ± 0.02 −8.4 ± 0.05 −8.5 ± 0.03 −7.7 ± 0.06 −11.9 ± 0.03
mol)
Interacting residues Tyr 1230*, Asp 1222 Leu 1157, Asp 1164, Ala 1226, Tyr Ile 1084, Tyr 1230*, Asp 1164 Val 1092, Ala 1108, Leu 1157, Tyr Val 1092, Ala 1108, Asp 1164, Ala 1221, Asp 1222, Tyr 1230*,
1230* 1230* Met 1160

Oncoprotein Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2- ABT-199

one

Average Binding Energy −7.4 ± 0.03 −8.5 ± 0.06 −7.7 ± 0.02 −7.1 ± 0.07 −12.2 ± 0.04
(kcal/mol)
Bcl-2 Interacting residues Asp 108, Leu 134, Phe 150, Leu 134, Ala 146, Arg Phe 101, Asp 108, Phe 109, Phe 109, Met 112, Phe 150, Glu Phe 101, Met 112, Val130, Leu 134, Arg 143, Val 145, Ala 146, Phe 150, Tyr
Phe 101* 143 Glu 133 149, Phe 101* 199, Asp 100, Tyr 105, Gly 142, Gln 96−, Asp 108+

Note: Amino acid residues forming: hydrophobic interactions are marked in italics, hydrogen bonds are highlighted in bold, π-stacking interactions are displayed with *, halogen bonds are marked with **, water bridges
are displayed with – and salt bridges are marked with +.
Computational Biology and Chemistry 78 (2019) 242–259
Md. M. Saleh-e-In et al. Computational Biology and Chemistry 78 (2019) 242–259

Fig. 3. Mode of interaction of graveolone and inhibitor TAK-285 with HER2. (A) Interaction of graveolone (yellow stick) and TAK-285 (blue stick) at the binding
pocket of HER2 (green ribbon). (B) Amino acid residues of HER2 interacting with graveolone. Hydrophobic interactions have been represented as grey dotted lines.
Blue lines represent hydrogen bonds (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Fig. 4. Mode of interaction of physcione and inhibitor dinaciclib with cyclin E. (A) Interaction of physcione (yellow stick) and dinaciclib (blue stick) at the binding
pocket of cyclin E (green ribbon). (B) Amino acid residues of cyclin E interacting with physcione. Hydrophobic interactions have been represented as grey dotted
lines. Blue lines represent hydrogen bonds (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

mol and -8.2 kcal/mol respectively with cyclin E protein at the active
site (Table 4). Thorough interaction profiling revealed promising in-
hibitory potential of the phytochemicals against cyclin E.
c-Met, involved in gastric cancer, displayed best docking score of
-8.5 kcal/mol with graveolone (Fig. 5 and Table 4) among the phyto-
chemicals. Rest of the compounds physcione, bergapten and 3-Ethyl-7-
hydroxy-chromen-2-one also interacted well c-Met showing moderate
binding energies of -8.4 kcal/mol, -7.9 kcal/mol and -7.7 kcal/mol re-
spectively (Table 4). Inhibitor triazolopyridazine, interacting at the ATP
binding cavity of c-Met (Albrecht et al., 2008), displayed a binding
energy of -11.9 kcal/mol. Meticulous in silico analysis revealed that all
the phytoconstituents interacted decently at the active site of c-Met,
reflecting probable inhibitory tendencies against the oncoprotein.
Bcl-2 protein, associated with cervical carcinoma, was found to
exhibit the best possible interaction with physcione (-8.5 kcal/mol)
among the phytochemicals (Fig. 6 and Table 4). Rest of the phytocon-
stituents graveolone, bergapten and 3-Ethyl-7-hydroxy-chromen-2-one
displayed moderate binding with Bcl-2 at the active site with binding
energies of -7.7 kcal/mol, -7.4 kcal/mol and -7.1 kcal/mol respectively.
Inhibitor ABT-199 was found to bind at the active site of Bcl-2 (Souers
et al., 2013) exhibiting a high binding efficacy of -12.2 kcal/mol.
3.4. Physicochemical properties of the phytochemicals and accordance with
the rules of drug-likeness
The physicochemical features of a potential therapeutic candidate
are considered to be vitally associated with its therapeutic precision,
safety and efficient metabolism (Gleeson et al., 2011; Doak et al., 2014;
van de Waterbeemd, 2009). Various features like molecular weight
(MW [dalton]), number of hydrogen bond acceptors (HBA) and donors
(HBD), number of rotable bonds, topological polar surface area
(TPSA[Å]) and logarithm of partial coefficient (log P) were estimated
thoroughly for the phytochemicals isolated from the root extracts of A.
Sowa (Table 5).
Physicochemical features were evaluated in light of the conven-
tional rules of drug-likeness that are applied in initial stages of drug
discovery, namely, Lipinski’s rule of Five (RO5), Veber’s rule, GSK 4/
400 rule and Pfizer 3/75 rule. Lipinski’s rule of Five (RO5) suggests that
a drug molecule tends to show decent oral bioavailability, smooth
membrane permeability and high gastrointestinal absorption in human
gut when its log P ≤ 5; MW ≤ 500 Da; HBAs ≤10 and HBDs ≤5
(Lipinski et al., 2001). Veber’s rule proposes that a therapeutic com-
pound with TPSA ≤ 140 Å and number of rotable bonds ≤ 10 should

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Fig. 5. Mode of interaction of graveolone and inhibitor triazolopyridazine with c-Met. (A) Interaction of graveolone (yellow stick) and triazolopyridazine (blue stick)
at the binding pocket of c-Met (green ribbon). (B) Amino acid residues of c-Met interacting with graveolone. Hydrophobic interactions have been represented as grey
dotted lines. Blue lines represent hydrogen bonds. π-stacking interactions are displayed as green dotted lines (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article).

Fig. 6. Mode of interaction of physcione and inhibitor ABT-199 with Bcl-2. (A) Interaction of physcione (yellow stick) and ABT-199 (blue stick) at the binding pocket
of Bcl-2 (green ribbon). (B) Amino acid residues of Bcl-2 interacting with physcione. Hydrophobic interactions have been represented as grey dotted lines. Blue lines
represent hydrogen bonds (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Table 5
Physicochemical properties of the phytochemicals isolated from Anethum sowa L. root extracts and their accordance with the rules of drug-likeness.
Physicochemical properties Compounds

Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2-one

No. of H bond acceptor (HBA) 4 5 4 3

No. of H bond donor (HBD) 0 2 0 1
TPSA (Ų) 52.58 83.83 56.51 50.44
No. of rotatable bonds 1 1 0 1
Mol. wt (dalton) 216.19 284.26 244.24 190.20
log P 1.93 3.04 1.98 2.36
Accordance with Lipinski’s rule of Five (RO5) Yes Yes Yes Yes
Accordance with Veber’s rule Yes Yes Yes Yes
Accordance with GSK 4/400 rule Yes Yes Yes Yes
Accordance with Pfizer 3/75 rule Warning Warning Warning Warning

Mol. wt- Molecular weight; TPSA- Topological Polar Surface Area; log P: Logarithm of partial coefficient.

possess high oral bioavailability (Veber et al., 2002). GSK 4/400 and suggests that the propensity of a drug tends to be toxic when its log
Pfizer 3/75 rules deal with prediction of probable toxicity based on the P > 4 and MW > 400 Da (Gleeson, 2008). Similarly, Pfizer 3/75 rule
physicochemical properties of a drug molecule. GSK 4/400 rule proposes that potential toxicity of a drug reduces when its log P < 3

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Md. M. Saleh-e-In et al. Computational Biology and Chemistry 78 (2019) 242–259

Table 6
Pharmacokinetic properties of the concerned phytochemicals isolated from Anethum sowa L. root extracts.
Pharmacokinetic properties Compounds

Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy-chromen-2-one

HIA High (98.34%) High (94.19%) High (98.36%) High (94.50%)

Solubility Soluble (Good) Soluble (Reduced) Soluble (Good) Soluble (Good)
Oral bioavailability (Veber) Good Good Good Good
Oral bioavailability (Egan) Good Good Good Good

HIA- Human intestinal absorption. HIA values (%) have been mentioned in parenthesis. HIA > 80%- high absorption and HIA < 25%- poor absorption.

Table 7
In silico toxicity assessment of the concerned phytochemicals isolated from Anethum sowa L. root extracts.
Toxicity assessment Compounds

Bergapten Physcione Graveolone 3-Ethyl-7-hydroxy chromen-2-one

Carcinogenicity No No No No
Medicinal Chemistry (PAINS) No alert 1 alert: quinone A No alert No alert
Mutagenicity (AMES Mutagenesis) Yes (High) Yes (Low) No No
Tumorigenicity Yes (High) No No No
Irritant No Yes (High) No No

PAINS- Pan-assay interference compounds.

and TPSA > 75 Å (Hughes et al., 2008).
Physicochemical properties of the concerned phytochemicals were
found to be in perfect accordance with Lipinski’s rule of Five (RO5) and
Veber’s rule, signifying their considerable drug-like potential (Table 5).
Complete accord with GSK 4/400 rule was indicative of their potential
non-toxic nature (Table 5). Furthermore, all the phytochemicals qua-
lified Pfizer 3/75 rule with one violation each in case of bergapten,
graveolone, 3-Ethyl-7-hydroxy-chromen-2-one (i.e., TPSA < 75 Å) and
physcione (i.e., log P > 3) (Table 5 and Supplementary Fig. S26). The
phytochemicals were all positioned in the non-toxic zone of the Pfizer
3/75 rule plot (TPSA [y-axis] plotted against log P [x-axis]) [Supple-
mentary Fig. S26]. Graveolone and physcione were found to display
decent potential drug-scores of 0.26 and 0.22 respectively in compar-
ison to bergapten which showed a low score of 0.09. 3-Ethyl-7-hydroxy-
chromen-2-one exhibited a high drug-score of 0.80. All the phyto-
chemicals, evaluated in the present study, successfully qualified the
drug-likeness parameters and initial toxicity prediction filters.
3.5. Analysis of pharmacokinetic features and potential toxicity
Drug absorption refers to the movement of a drug from the extra-
vascular site of administration to the circulating blood stream from
where it can reach its destined site of action (Lagorce et al., 2011;
Gleeson, 2008). In silico assessment of intestinal absorption revealed
that all the phytochemicals were potentially highly absorbed in the
human gastrointestinal tract (Table 6). Our observations of high in-
testinal absorption for bergaptene and physcione seemed well justified
in light of previous evidences (Petit et al., 2016; Wang et al., 2017).
Solubility in intestinal fluid is a crucial factor governing the efficiency
of an oral drug (Gleeson, 2008). Low solubility has been inferred to
result in poor intestinal absorption (Kerns et al., 2004; Chevillard et al.,
2012) and inadequate exposure of an oral drug (Lesson, 2016). Esti-
mation of solubility revealed that all the concerned compounds, except
physcione (reduced solubility), were highly soluble (Table 6). Decent
oral bioavailability was evident for all the compounds according to the
prediction schemes proposed by Veber et al. (2002) and Egan et al.
(2000) (Table 6).
Proper know-how and investigations regarding clinical safety of a
novel therapeutic candidate is one of the most critical aspects in the
field of drug development (Blomme and Will, 2016; Blagg, 2010). At-
trition pertaining to drug toxicity is a major impediment leading to
rejection of a large number of therapeutic components at a later phase
of drug development (Blomme and Will, 2016; Waring et al., 2015).
After successful delivery of drugs in the human system, major toxic
effects like carcinogenicity, mutagenicity and tumorigenicity (Benigni
and Bossa, 2011; Liebler and Guengerich, 2005) have been issues of
severe concern. Accordingly, in silico toxicity prediction and assessment
of novel drug candidates have been suggested to be meaningful in the
nascent phases of drug development (Wang et al., 2015).
Carcinogens are referred to as the chemicals/compounds that in-
duce formation, growth and proliferation of tumours, thus, stimulating
cancer (Kroes et al., 2004). Comprehensive in silico toxicity estimation
of the phytochemicals revealed that all of them were potential non-
carcinogens (Table 7). In this pretext, it is worth mentioning that po-
tential carcinogenicity of bergaptene and physcione is still matter of
debate and further evidences are required to arrive at any definite
conclusion (Averbeck et al., 1990; Navarra et al., 2015; Locatelli,
2011). Identification of compounds with structural alerts is an im-
perative screening step of drug development. PAINS compounds (pan-
assay interference compounds) are commonly referred to as tox-
icophores with alarming chemical groups that have been reported to
interfere with biological assays, interact and damage DNA/proteins and
subsequently, lead to several threatening consequences like hepato-
toxicity, carcinogenicity and CYP inhibition (Baell, 2010; Pouliot and
Jeanmart, 2016). The concerned phytochemicals, except physcione
(displaying 1 alert- quinone A), were not found to possess any PAINS
structural alert (Table 7), thus, successfully qualifying the PAINS re-
lated toxicity screening step.
Mutagenicity refers to the adversities of genetic mutation on ex-
posure to chemicals that induce such mutative effects (Ames et al.,
1973). In silico mutagenicity assessment, in correlation with Ames
mutagenicity dataset, was achieved employing ProTox-II web-server
and results were further validated with admetSAR. Strikingly, bergap-
tene and physcione were predicted to be mutagenic. Our observations
correlated well with previous reports pertaining to strong mutagenic
and genotoxic behaviour of bergaptene and weak mutagenic potential
of physcione (Averbeck et al., 1990; Navarra et al., 2015; Locatelli,
2011). However, graveolone and 3-Ethyl-7-hydroxy-chromen-2-one
were assessed to be potential non-mutagens (Table 7). Bergaptene was
also estimated to be tumorigenic (Table 7) which correlated well with
previous reports (Averbeck et al., 1990; Navarra et al., 2015). On the
other hand, physcione was predicted to show potential irritation effects

255
Md. M. Saleh-e-In et al.
from the in silico investigations.
Graveolone and 3-Ethyl-7-hydroxy-chromen-2-one were found to be
potentially safe and non-toxic from the array of in silico toxicity as-
sessments performed in the present study. However, further experi-
mental evidences would consolidate such predictions pertaining to their
non-toxic nature.
4. Conclusion
Natural compounds are regarded as principal sources for drug in-
vestigation and contribute significantly for novel drug design and de-
velopment programs. Efficient drug design and development depends
largely on the availability of natural compounds and subsequent iso-
lation. The present research endeavour deals with the isolation of seven
compounds including a new compound 4 from the root extracts of A.
sowa. Coumarins and anthraquinones were isolated as the main che-
mical constituents of fractions. All the isolated compounds were iden-
tified for the first time from the roots of A. sowa. Among the isolated
compounds, physcione and bergapten and their associated synthetic
derivatives have been previously reported to be of immense pharma-
cological importance. Physcione and bergapten have been observed to
be associated with some imperative bioactivities including anticancer
potential. Accordingly, in silico investigation (encompassing molecular
docking and profiling of drug-likeness) was extensively performed to
infer about the prospect of targeting the isolated phytochemicals
against various forms of cancer. Interestingly, majority of the isolated
compounds were found to display decent binding efficacies with on-
cogenes involved in various forms of carcinoma, namely, breast, liver,
gastric and cervical cancers. However, proper estimation of drug-like-
ness features and profiling of potential toxicity revealed that graveolone
might establish itself as a promising therapeutic molecule based on
binding energy scores and its non-toxic attributes. Phytochemical in-
vestigations and pertaining in silico studies of the root extracts of A.
sowa might bolster the drug development platform against cancer.
Present work, aided by molecular docking and pharmacokinetic in-
vestigations, reveals promising anticancer potential of the isolated
compounds from the roots of A. sowa against conventional oncogenes.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
The authors would like to thank the Bangladesh Council of Scientific
and Industrial Research for awarding the Dr. Qudrat-i-Khuda a doctoral
fellowship and University of Kwazulu Natal for Postdoctoral fellowship
for this research work.
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