Design, cytotoxic effects on breast cancer cell line (MDA-MB 231), and molecular docking of some maleimide-benzenesulfonamide derivatives

Article abstract of DOI:10.1016/j.jics.2021.100055

A group of novel maleimide-benzenesulfonamide derivatives 3a-d was designed and synthesized for their evaluation as a potential anti-breast cancer agent. The structures of these derivatives were confirmed by their ¹H, ¹³C NMR, Mass, FT-IR spectral data, and melting points. The cytotoxic activity (in vitro) of the selected molecules against MDA-MB231 ?cell line was evaluated by MTT method. Among them, compounds 3a and 3d exhibited a significant cytotoxicity with the IC₅₀ value of 1.61 and 1.26 ?μM, respectively, whereas compounds 3b and 3c showed a moderate cytotoxicity with IC₅₀ values of 0.45 and 1.12 ?μM, respectively against MDA-MB231 ?cells. Docking modeling of the synthesized compounds 3a-d into binding sites of human aromatase protein (PDB ID: 4GL7) was performed to investigate if these derivatives possess analogous binding mode to breast cancer proteins. Docking results showed these compounds have efficient interactions such as hydrogen bonding, Van der Waals interactions, and hydrophobic interactions with the active site residues of the aromatase protein (PDB ID: 4GL7). The low binding energies and a number of hydrogen bonding indicated that the maleimide-benzenesulfonamide derivatives might be considered as a promising anti-breast cancer agent with further developments in drug discovery.

Full text of DOI:10.1016/j.jics.2021.100055

Journal of the Indian Chemical Society 98 (2021) 100055
Contents lists available at ScienceDirect
Journal of the Indian Chemical Society
journal homepage: www.editorialmanager.com/JINCS/default.aspx
Design, cytotoxic effects on breast cancer cell line (MDA-MB 231), and
molecular docking of some maleimide-benzenesulfonamide derivatives
*
Adil M. Dhumad, Ahmed M. Jassem , Raed A. Alharis, Faeza A. Almashal
Department of Chemistry, College of Education for Pure Sciences, University of Basrah, Basrah, Iraq
A R T I C L E I N F O
A B S T R A C T
Keywords:
Breast cancer
MDA-MB231
Cytotoxicity
Molecular docking
Maleimide-benzenesulfonamide derivatives
A group of novel maleimide-benzenesulfonamide derivatives 3a-d was designed and synthesized for their eval-
uation as a potential anti-breast cancer agent. The structures of these derivatives were confirmed by their 1H,
13
C
NMR, Mass, FT-IR spectral data, and melting points. The cytotoxic activity (in vitro) of the selected molecules
against MDA-MB231 cell line was evaluated by MTT method. Among them, compounds 3a and 3d exhibited a
significant cytotoxicity with the IC50 value of 1.61 and 1.26
showed a moderate cytotoxicity with IC50 values of 0.45 and 1.12
Docking modeling of the synthesized compounds 3a-d into binding sites of human aromatase protein (PDB ID:
GL7) was performed to investigate if these derivatives possess analogous binding mode to breast cancer proteins.
μ
M, respectively, whereas compounds 3b and 3c
μ
M, respectively against MDA-MB231 cells.
4
Docking results showed these compounds have efficient interactions such as hydrogen bonding, Van der Waals
interactions, and hydrophobic interactions with the active site residues of the aromatase protein (PDB ID: 4GL7).
The low binding energies and a number of hydrogen bonding indicated that the maleimide-benzenesulfonamide
derivatives might be considered as a promising anti-breast cancer agent with further developments in drug
discovery.
1. Introduction
features that offer various types of biological and pharmaceutical appli-
cations [9]. Their structures include an imide group with the general
Cancer disease has been identified as one of the major reason for
structure –CO–N(R)–CO–, therefore they can confer various electronic
environments and cross biological membranes [10]. A number of natural
products such as staurosporine [11] and polycitrin [12] that exhibit
medicinal applications contain maleimide as an important part in their
structures. Examples of biological activities of maleimide derivatives
include inhibitors as they show a selective inhibitory effect toward
various proteins for examples a membrane enzyme (cyclooxygenase,
COX-2) that is produced in the biosynthesis of prostaglandin [13] and
enzyme kinase that plays a vital role in an intracellular signaling mech-
anism of all living organisms [14].
On the other hand, sulfonamide and its derivatives are a versatile
structure for their diverse pharmaceutical activities [15], and these
compounds are in clinical use as antibacterial [16], anti-inflammatory
[17], antihypertensive [18], anti-glaucoma agents, and carbonic anhy-
drase inhibitors (CAIs) [19]. Furthermore, some novel sulfonamide de-
rivatives have been reported to exhibit anticancer activities [20,21].
The synthesis of potent anticancer molecules has emerged as an
efficient protocol for breast cancer treatment. The combination of phar-
maceutical molecules is employed in drug discovery for identifying target
mortality in the worldwide [1]. Metastatic breast cancer is commonly
called breast cancer, characterized as an untreatable disease by
current-treatment procedures [2]. In United States and other European
countries, this disease is diagnosed as a malignant disease, according to
WHO statistics, cases of death in female accounting for >400 each year
[
3]. The cure strategies of breast cancer normally includes healing pro-
cedures such as radiotherapy, immunotherapy, chemotherapy, and sur-
gery [4]. Unfortunately, the majority of drugs that have been given to
patients are somewhat toxic and their uses are associated with severe side
effects. These side effects are becoming as a major obstacle to decrease
the use of chemotherapeutic agents for breast cancer [5]. Thus, there is a
desirable require to discover effective anticancer drugs by continuously
designing novel compounds and testing them toward breast cancer dis-
ease [6]. Moreover, the design and synthesis of novel like drugs with
potential anti-breast cancer are a persistent need for the most medicinal
chemists [7].
Maleimide and its derivatives are known as one of the important
heterocyclic compounds [8]. These compounds possess structural
*
Corresponding author.
E-mail address: ahmed.majedd@uobasrah.edu.iq (A.M. Jassem).
https://doi.org/10.1016/j.jics.2021.100055
Received 20 March 2021; Received in revised form 1 May 2021; Accepted 10 May 2021
019-4522/© 2021 Indian Chemical Society. Published by Elsevier B.V. All rights reserved.
0

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 1. Some pharmacologically active maleimides bearing sulfonamide moiety.
Scheme 1. Synthesis of maleimide benzenesulfonamide hybrid molecules 3a-d.
Fig. 2. The evaluation of IC50 values for the synthesized molecules 3a-d by GraphPad Prism 8.10 with a statistical significance (values of *p < 0.05).
various diseases. The combination of two or more pharmacophores could
offer a high potential for the inhibition of a number of diseases, especially
for tumor and cancer diseases [22]. The connection of known pharma-
cophore for example sulfonamide with some cyclic amides enhances the
physiochemical properties of the expected like-drugs, thus this request is
becoming a challenging perspective in drug discovery [23].
describe the bioactivity shown by maleimide and sulfonamide hybrids
[24]. The combination of maleimide and sulfonamide provides efficient
building blocks in organic and medicinal chemistry with pronounced
broad spectrum of biological activities. For example, maleimide deriva-
tive (A) that bears a sulfonamide moiety showed potent activities such as
COX-2 inhibitor and anti-inflammatory activity [25]. Recently, a group of
maleimide derivatives (B) bearing sulfonamide moiety has been designed
and tested for in vitro anticancer activity toward human cancer cell lines,
Although maleimide moiety has not been showing to be combined
with sulfonamide so far, literature has recently viewed some works that
2

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 3. Optimized structures of maleimide sulfonamide hybrid molecules 3a-d.
Table 1
H-Bond count and affinity energies of the targeted molecules 3a-d and anasro-
zole drug inside the human placental aromatase structures (PDB ID: 4GL7).
Comp.
Affinity
energy
Protein-molecule interaction by
H-bonds
Protein-molecule
interaction by Van der
Waals forces
(kcal/
mol)
ꢀ8.5
ꢀ7.1
No. of
H-
bonds
Amino
acid
residues
Distance
(A )
Amino
acid
residues
No.
Amino
acid
o
residues
3
3
a
b
7
2
Gly439
Arg145
Ile133
Arg435
Ile132
2.97
2.94
3.09
3.15
3.11
3.13
3.00
Cys437,
Gly436,
Ala306,
Ala438,
Arg115
Trp224,
Phe221,
Ser478,
Leu477,
Val370,
Ile133,
5
Ala306
Thr310
8
Fig. 4. Graphical diagram of Mulliken charges of heavy atoms for the com-
pounds 3a-d.
Gly439,
Ala443
Ile132,
including lung (NCl H-522), ovary (PA-1), colon (HCT-15), breast
3
3
c
ꢀ8.1
ꢀ7.2
4
4
Gly439
Ala438
Gly436
Arg145
3.08
3.17
2.79
3.02
8
(
T47D), liver (Hep G2) and the results showed that the synthesized
Ile133,
compounds have a potency against these types of cancer (Fig. 1) [26].
The available methods for the synthesis of maleimide sulfonamide
hybrids generally call that an amine part of sulfonamide structure is
firstly reacted with the selected cyclic anhydrides to result amic acids.
The resulting amic acids can be further cyclized to afford the corre-
sponding maleimide sulfonamide hybrids. In these methods some cata-
lysts have been explored in the synthesis of novel maleimide sulfonamide
Phe221,
Thr310,
Trp224,
Asp309,
Ala306,
Cys437
Ala307,
Ala306,
Met303,
Leu152,
Ala438,
Ala443,
Phe430,
Val370,
Met447,
Met364
Ala438,
Cys437,
Gly436,
Ile133,
d
Gly439
Thr310
Ser314
Ser314
3.02
2.90
3.25
3.26
10
hybrids, including H6P2W18O62 [24], [Bmim] [27], Et
cyanuric chloride/Et [29], and dimethyl sulfate/Na
trabutylammonium bromide [30].
3
N/Ac
2
O [28],
CO /te-
3
N
2
3
In continuation to our ongoing interest in search of bioactive mal-
eimide sulfonamide hybrids against breast cancer, we have synthesized
some novel maleimide sulfonamide molecules (3a-d) using a facile
method with cheapest catalyst in a one-pot synthesis. The aim of syn-
thesizing these hybrid molecules is to investigate potential anticancer
effect with a potency against breast cancer. Thus, we report the cyto-
toxicity of these hybrid molecules on human cell line (breast cancer,
MDA-MB 231). Also, these molecules were docked into human aromatase
protein (PDB ID: 4GL7) binding site by using in silico method.
Anasrozole
ꢀ7.8
2
Arg145
Arg115
3.12
2.95
10
Thr310,
Val370,
Trp224,
Phe134,
Ile132,
2. Materials and methods
Ala306
All the chemicals and solvents were used as received from Sigma-
3

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 5. (a) 2D Interactions of molecule 3a with aromatase protein using LigPlot þ version, (b) ligand-receptor interactions (3D) of molecule 3a with aromatase protein
using PyMOL program (2.0 Schr o€ dinger-LLC), and (c) interactions of molecule 3a with aromatase protein as a surface carton using PyMOL program.
Fig. 6. (a) 2D Interactions of molecule 3b with aromatase protein using LigPlot þ version, (b) ligand-receptor interactions (3D) of molecule 3b with aromatase protein
using PyMOL program (2.0 Schr o€ dinger-LLC), and (c) interactions of molecule 3b with aromatase protein as a surface carton using PyMOL program.
4

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 7. (a) 2D Interactions of molecule 3c with aromatase protein using LigPlot þ version, (b) ligand-receptor interactions (3D) of molecule 3c with aromatase protein
using PyMOL program (2.0 Schr o€ dinger-LLC), and (c) interactions of molecule 3c with aromatase protein as a surface carton using PyMOL program.
Aldrich without a further purification. Analytical properties of thin layer
chromatography (TLC) were completed by using plates coated with a
silica gel 60 UV 255. The dot spots of the synthesized compounds were
checked by either UV light or an alkaline aqueous solution of potassium
permanganate (KMnO4). Melting points for all synthesized compounds
were checked by using a Gallenkamp melting point apparatus. In the
(500 MHz, DMSO-d6) δ 7.93 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.57 (d, J ¼ 8.3
–
2
–
Hz, 2H, Ar-H), 7.44 (s, 2H, NH ), 7.23 (s, 2H, H–C C); IR (KBr) cm :
ꢀ1
–
–
3369, 3265 (N–H), 3099 (C–H, Ar), 3055 (H–C
–
C), 1724 (C
–
O), 1408
þ
(C–N); EI-MS m/z (%), M [C10
H
8
N
O
2 4
S], 252 (100), 236 (98), 144
(37.8), 116 (39.3), 172 (98), 54 (15).
ꢀ1
range 4000-500 cm , the FT-IR spectra were run on Shimadzu FT-IR
2.3. N-(4,6-Dimethylpyrimidin-2-yl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-
1-yl)benzene sulfonamide (3b)
1
8
5
400S spectrometer using KBr disc. H NMR spectra were run on Bruker
00 spectrometer (Iran) using tetramethylsilane (TMS) and DMSO-d6 as
ꢁ
1
an internal reference and solvent, respectively. The splitting prefixes are
addressed as (s, for singlet), (d for doublet) and (m for multiplet). Mass
spectra for the synthesized compounds were recorded on Agilent Tech-
nologies-5975C (EI, 70 eV) (Iran).
Isolated as a pale solid; yield (60%), m.p 174–175 C; H NMR (500
MHz, DMSO-d6) δ 12.04 (s, 1H, NH), 8.08 (d, J ¼ 7.9 Hz, 2H, Ar-H), 7.55
–
(d, J ¼ 8.7 Hz, 2H, Ar-H), 7.22 (s, 2H, H–C
–
C), 6.75 (s, 1H, Ar-H), 2.25
13
–
); C NMR (126 MHz, DMSO-d6) δ 172.0 (C
–
(s, 6H, 2CH
3
O, amide),
–
–
3
69.5 (C N, pyrimidine), 155.9 (C–N ), 139.8 (C–S), 134.9 (C–N),
1
–
–
–
–
C, pyrimidine), 22.6 (CH
2
.1. General method for synthesis of maleimide benzenesulfonamide
128.7 (C
–
C, Ar), 125.9 (C
–
C), 113.0 (C
–
(KBr) cm : 3263 (N–H), 3101 (C–H, Ar), 3000 (H–C
–
3
); IR
C), 2800 (C–H),
–
þ
–
14 4 4
O), 1396 (C–N); EI-MS m/z (%), M [C16H N O S], 358
ꢀ
1
derivatives (3a-d) [31]
1714 (C
To a three-neck round-bottom flask charged with maleic anhydride 1
25.0 mmol) and DMF (20 mL), primary amine benzenesulfonamides 2a-
(30.9), Mþ1359 (5.9), 293 (100).
(
d (25.0 mmol) was added. The reaction mixture was stirred at room
temperature for 2 h. The precipitated corresponding sulfonamic acids
were obtained by suction filtration. Without any further purification, the
obtained sulfonamic acid (12.0 mmol) was subsequently cyclized in the
presence of acetic anhydride (15 mL) and sodium acetate (9.5 mmol) on a
2.4. N-((4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)sulfonyl)
acetamide (3c)
ꢁ
1
Isolated as a yellowish solid; yield (54%), m.p 163–164 C; H NMR
(500 MHz, DMSO-d6) δ 12.21 (s, 1H, NH), 8.03 (d, J ¼ 8.3 Hz, 2H, Ar-H),
ꢁ
–
steam bath (70–80 C) for 3 h. The resulting mixture was cooled to room
7.64 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.24 (s, 2H, H–C
–
C), 1.95 (s, 3H, CH
3
);
13
–
–
–
O, amide), 168.9 (C
–
temperature and poured into an ice water. The formed precipitate was
collected by filtration, recrystallized from methanol, and dried under
vacuum to afford the titled maleimide benzenesulfonamide molecules
C NMR (126 MHz, DMSO-d6) δ 169.4 (C
O),
C, Ar), 126.5
–
–
3
(C C), 23.3 (CH ); IR (KBr) cm : 3358 (N–H), 3055 (C–H, Ar), 3033
–
–
–
–
137.8 (C–S), 136.0 (C–N), 135.0 (C
C, Ar), 128.4 (C
ꢀ1
–
–
–
C), 2850 (C–H) 1730 (C O), 1405 (C–N); EI-MS m/z (%),
S], 294 (3.6), 230 (10.8), 172 (33.7), 189 (100).
3a-d.
(H–C
–
þ
M [C12
H
10
N
2
O
5
2
.2. 4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzenesulfonamide (3a)
Isolated as a yellow solid, Yield (62%), m.p 156–157 C. 1H NMR
ꢁ
5

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 8. (a) 2D Interactions of molecule 3d with aromatase protein using LigPlot þ version, (b) ligand-receptor interactions (3D) of molecule 3d with aromatase protein
using PyMOL program (2.0 Schr o€ dinger-LLC), and (c) interactions of molecule 3d with aromatase protein as a surface carton using PyMOL program.
2
.5. N-Carbamimidoyl-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)
2.9. Theoretical and docking calculations
benzenesulfonamide (3d)
Gaussian 09 software package has been employed to accomplish the
theoretical calculations [32]. The electronic structures and full geometry
optimizations for the synthesized molecules were accomplished by using
density function theory (DFT) with 6–311þþG (d,p) basis set. Hybrid
functional B3LYP method has been used to identify the potential
exchange-correlation [33,34]. The aromatase protein was obtained from
the open access digital resource protein data bank by downloading the
PDB file. The 3D structure of target aromatase protein (PDB ID: 4GL7)
was generated through homology modeling. Polar hydrogen atom was
added to understand the interactions between the synthesized molecules
and the target aromatase protein (PDB ID: 4GL7). The optimized hybrid
molecules 3a-3d were docked into a target protein (PDB ID: 4GL7) as an
adrenal enzyme which acts to convert androstenedione and estrone to
estrogen. The 3D structure of anasrozole was downloaded from htt
ps://pubchem.ncbi.nlm.nih.gov as SDF file which was converted to
protein data bank file (PDB) by using discovery studio 2017 R2 Client.
Anasrozole drug was also docked into the same target aromatase protein
Isolated as a colorless solid; yield (54%), m.p 163–164 C; 1H NMR
500 MHz, DMSO-d6) δ 7.85 (d, J ¼ 6.2 Hz, 2H, Ar-H), 7.66 (s, 2H, NH ),
C), 2.07 (s, 1H, NH); IR
(
1
ꢁ
(
7
2
–
–
.48 (d, J ¼ 6.8 Hz, 2H, Ar-H), 7.22 (s, 2H, H–C
ꢀ1
–
KBr) cm : 3489, 3433, 3336 (N–H), 3100 (C–H, Ar), 3050 (H–C C),
–
–
þ
714 (C O), 1398 (C–N); EI-MS m/z (%), M [C11H N O S], 294.1
–
10 4 4
7.8), Mþ1295 (3.1), 230 (15.6), 106 (31.2), 43.1 (100).
.6. Cell culture
The cell lines of MDA-MB 231 were kept in 10 cm plate involving
(
2
DMEM and equipped with 100
μ
g/mL streptomycin, 100 units/mL
penicillin, and 10% FBS at 36 C under a humid atmosphere (CO
ꢁ
2
, 5%).
2
.7. Dose response and cytotoxicity
MDA-MB 231 cells were maintained in 48 wells/plate and subjected
to each selected compound (0–250 M) for 48 h. Micro-plate reader
Thermo Scientific) was used to determine the cell viability at 570 nm
and the all experiments were carried out in three times [6].
(
PDB ID: 4GL7) for comparative purposes. Autodock Vina (AutoDock 4.2
μ
package) was applied for molecular docking to understand the
protein-molecules interactions.
(
3
. Results and discussion
2
.8. Statics analysis
3
.1. Chemistry
The collected data were expressed by a mean ꢂ SEM and the
GraphPad Prism 8.10 was taken with a statistical significance (values of
*
Maleimide benzenesulfonamide derivatives 3a-d (Scheme 1) were
p < 0.05).
6

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
Fig. 9. (a) 2D Interactions of anasrozole drug with aromatase protein using LigPlot þ version, (b) ligand-receptor interactions (3D) of anasrozole drug with aromatase
protein using PyMOL program (2.0 Schr o€ dinger-LLC), and (c) interactions of anasrozole drug with aromatase protein as a surface carton using PyMOL program.
synthesized from the reaction of maleic anhydride 1 and various amine
benzenesulfonamides 2a-d by stirring the mixture in acetone at tem-
perature room for 2 h. After, the precipitated corresponding sulfonamic
acids were formed, the resulting sulfonamic acids were treated with
cancer cells (MDA-MB231) [36]. This could be expressed to their
disparity in either bioavailability or binding site properties of enzymes.
The IC50 values of the cytotoxic screen for the synthesized derivatives
being closer to those resulted from doxorubicin (reference antineoplastic
ꢁ
acetic anhydride and sodium acetate under heating (70–80 C) for 3 h
drug) [37] against anti-breast cancer cell line (IC50 ¼ 1.30 ꢂ 0.3 μM), in
over a steam path. The formation of the corresponding maleimide ben-
zenesulfonamide molecules 3a-d was indicated by progress TLC with
hexane/ethyl acetate (8:2, v/v) as an eluent. After the purification was
other words, these hybrid molecules may be considered as promising
anti-breast cancer agents.
1
completed, the structures of these molecules were depicted by their H,
3.3. Molecular docking results
1
3
C NMR, FT-IR, and mass spectra. The spectra data of these molecules
were in consistent with their expected structures (see supporting
information).
Molecular docking data help to understand the ligand-enzymes in-
teractions, predict a potential binding geometry for each agent at the
active site of protein, and provide an efficient access to design novel
potent inhibitors [38]. To achieve this goal, molecular docking was
performed on the active site of human placental aromatase structures
(PDB ID: 4GL7) using AutoDock 4.2 [39]. Firstly, DFT/B3LYP calcula-
tions and the 6-311G (d,p, a basis set) have been used to optimize the
structural geometries of the synthesized molecules 3a-d. The optimized
structures of these molecules are configured in Fig. 3.
3
.2. Cytotoxicity on breast cancer cells line
The synthesized maleimide benzenesulfonamide hybrids 3a-d were
selected for the next step of our main purpose in order to evaluate their
cytotoxic effects in an in vitro toward MDA-MB231 cell line using MTT
test [35].
After 48 h of the treatment with 0–250
μ
M of these molecules,
Mulliken charges of heavy atoms for the compounds 3a-d have been
calculated using DFT/B3LYP method with 6-311þG(d,p) basis set level.
The results are given in Fig. 4 which show that oxygen and nitrogen
atoms have the highest negative value in terms of charge compared to
other atoms the compounds 3a-d, and this indicated that the oxygen and
nitrogen are the most electronegative atoms for forming hydrogen bonds
with amino acids in the active sites of the target proteins.
The aromatase protein has been considered as a useful therapeutic
target in the treatment or prevention of estrogen-dependent breast cancer
[40]. The important interactions between the synthesized molecules and
GraphPad Prism 8.10 has been applied to estimate the values of IC50. The
resulted data showed that the compounds 3a and 3d exhibited a signif-
icant cytotoxicity toward MDA-MB231 cells with IC50 values of 1.60 and
1
3
.26
μ
M respectively, while a moderate cytotoxicity for the compounds
b and 3c with IC50 values of 0.45 and 1.12
μ
M, respectively. From the
GraphPad Prism 8.10 data (Fig. 2), the nature of the combination of
maleimide moiety with the sulfonamide residue affects the relevance of
cytotoxicity. Observably, the compound 3a with free substitution at
sulfonamide part enhances the efficiency of cytotoxicity on the breast
7

A.M. Dhumad et al.
Journal of the Indian Chemical Society 98 (2021) 100055
the aromatase protein were calculated by using LigPlotþ and PyMOL
programs in order to evaluate docking efficiency [41,42]. The affinity
cytotoxic behavior toward breast cancer cells (MDA-MB231). Docking
studies of the synthesized molecules were performed with the human
aromatase protein homology model (PDB ID: 4GL7). The docking data
that collected from the synthesized molecules with the aromatase protein
were compared with the docking data those calculated from anasrozole
drug with the same protein. It was found that these molecules insert deep
inside the aromatase protein-pocket and forming strong hydrogen bond
interactions with the essential amino acid residues of protein active site.
The docking results also showed that the maleimide benzenesulfonamide
molecules offered significant interactions such as hydrophobic in-
teractions and Van der Waals forces with the aromatase protein. This
outcome indicates that the synthesized maleimide benzenesulfonamide
derivatives might be considered as a promising anti-breast cancer (MDA-
MB231) agent.
(
binding energies) of the hybrid molecules 3a-d with the active site of
aromatase protein was evaluated from molecular docking calculations.
The values of the binding energies in the active site were, ꢀ8.5, ꢀ7.1,
ꢀ1
ꢀ
8.1, and ꢀ7.2 kcal mol for hybrid molecules 3a, 3b, 3c, and 3d,
respectively. The affinity and binding interactions via hydrogen bonding
and hydrophobic interactions are displayed in Table 1. The lower binding
energy values of the molecules 3a and 3c elucidated that these molecules
interacted with target protein to consist a stable complex system. Anas-
rozole is a well-known drug, commonly called nonsteroidal aromatase
inhibitor which is used in the inhibition of breast cancer. This drug was
also docked with the same target aromatase protein (PDB ID: 4GL7) for a
comparative target with the results those calculated from the synthesized
molecules 3a-d.
A comparison of the molecular docking data for the synthesized
molecules 3a-d and anasrozole drug with the target aromatase protein
based on the binding energy values and a number of hydrogen bond
interactions was extensively investigated. It was found that molecules 3a
and 3c have higher (negative) energy than anasrozole drug. The calcu-
lated binding energies for the synthesized molecules 3a, 3b, 3c, and 3d
are ꢀ8.5, ꢀ7.1, ꢀ8.1, and ꢀ7.2 kcal mol that indicate the molecules
exhibit a perfect and selective binding into the active site of human
placental aromatase protein (PDB ID: 4GL7) as listed in Table 1. Also,
docking results showed that the synthesized molecules 3a-d interacted
with the receptor by several hydrogen bonds and hydrophobic in-
teractions. The active pocket of the human aromatase protein includes
amino acid residues such as Gly439, Arg145, Ile133, Arg435, Ile132,
Ala306, Thr310, Ala438, Gly436, Ser314, and Arg115 which play a vital
role in binding through hydrogen bonding and hydrophobic interactions.
The docked molecule 3a was found to have seven hydrogen bonds,
Funding
This work was financially supported by the authors.
Declaration of competing interest
ꢀ
1
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
Authors gratefully thank to biochemist staff of University of Gov-
ernment, Faisalabad 3800, Pakistan (Department of Cytology, Molecular
Biology Lab) for completing the screen of compounds against breast
cancer (cell lines).
ꢁ
ꢁ
ꢁ
including Gly439 (2.97 A ), Arg145 (2.94 A ), Ile133 (3.09 A ), Arg435
ꢁ
ꢁ
(
3.15 A ), and Ile132 (3.11 A ). While the other docking molecules
showed two hydrogen bonds for molecule 3b with Ala306 (3.13 A ) and
Appendix A. Supplementary data
ꢁ
ꢁ
Thr310 (3.00 A ), four hydrogen bonds for molecule 3c with Gly439
Supplementary data to this article can be found online at https://do
i.org/10.1016/j.jics.2021.100055.
ꢁ
ꢁ
ꢁ
ꢁ
(
3.08 A ), Ala438 (3.17 A ), Gly436 (2.79 A ), and Arg145 (3.02 A ), as
ꢁ
well as four hydrogen bonds for molecule 3d with Gly439 (3.02 A ),
ꢁ
ꢁ
ꢁ
Thr310 (2.90 A ), Ser314 (3.25 A ), and Ser314 (3.26 A ). Moreover,
additional interactions (Van der Waals forces) were formed between the
synthesized molecules 3a-d and the amino acid residues (No. 5–10). The
visual output interactions of the synthesized molecules 3a-d with the
aromatase receptor have been analyzed by using LigPlotþ and PyMol
programs. The residues interactions of the molecules 3a-d with the
aromatase receptor (PDB ID:4GL7) by Van der Waals forces were
configured as labeled arcs with radial spokes (2D interactions by LigPlot
þ program) as shown in Figs. 5–9, A. The PyMOL molecular graphics
system is applied to provide 3D molecule-protein interactions as
configured in Figs. 5–9, B. Furthermore, the aromatase receptor surfaces
are depicted as a cartoon (Figs. 5–9, C), showing the electrostatic prop-
erties and the size of binding pocket.
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9