Informatics in Medicine Unlocked 36 (2023) 101159

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Informatics in Medicine Unlocked

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Selective modification of diclofenac to reduce the adverse effects; A

computer-aided drug design approach
Md. Kamrul Hasan a, c, Shamima Akhter a, c, Kaniz Fatema b, c, Md. Rezaul Hossain a, c,
Tamanna Sultana b, c, Monir Uzzaman c, d, *
a
Department of Theoretical and Computational Chemistry, University of Dhaka, Dhaka, 1000, Bangladesh
b
Department of Pharmacy, Comilla University, Comilla, 3506, Bangladesh
c
Department of Drug Design, Computer in Chemistry and Medicine Laboratory, Dhaka, Bangladesh
d
Faculty of Science, Department of Chemistry, University of Chittagong, Chittagong, 4331, Bangladesh

A R T I C L E I N F O A B S T R A C T

Keywords: Diclofenac (DCF) is a non-steroidal anti-inflammatory drug (NSAID), commonly used for the treatment of pain. It
Diclofenac can inhibit prostaglandin synthesis by blocking cyclooxygenase (COX). It shows some crucial side effects like
Cyclooxygenase gastrointestinal, cardiovascular, renal, and liver injury. The gastrointestinal injury occurred due to the presence
Molecular docking and dynamic simulation
of a carboxylic (COOH) group at the core of DCF. The hydroxyl (OH) portion of COOH was replaced by inserting
ADMET and PASS prediction
some new functional groups (CH3, OCH3, CH2NH2, NH2, NHCOCH3, NHCONH2, Cl, CF3) considering the ret­
rosynthetic strategy which reduces gastrointestinal side effects with improved chemical and biological activity.
Herein, we have investigated the physicochemical, spectral, molecular dynamics, biological and pharmacokinetic
properties of the mentioned analogues. Density functional theory (DFT) and time-dependent DFT along with the
B3LYP/6-31g (d,p) basis set have been utilized to calculate their geometrical, chemical, and spectral properties.
Molecular docking and non-bonding interactions have been performed against human prostaglandin synthase
protein (PDB ID: 5F1A) to investigate their binding affinities, modes, and stability. ADMET and PASS prediction
studies were performed to investigate their microbial inhibition and toxicological profile. Quantum chemical
calculations and spectral characterization support the geometry of newly designed analogues. From the mo­
lecular docking simulation, most of the analogues exhibited better binding affinity than the parent drug except
for DCF-2. ADMET calculations predict the improved pharmacokinetic and non-carcinogenic properties of all
DCF analogues. Biological activities and drug-likeness indicate that all the analogues of DCF have been exposed
to comparatively lower action of the gastrointestinal hemorrhage than DCF and exhibit antipyretic, analgesic,
and anti-inflammatory actions as well as performed to overcome the poor absorption or permeation of drugs.
Finally, based on the above investigation, this study can be helpful to design a potential drug candidate with
improved medicinal action and reduced selective adverse effects.

1. Introduction ankylosing spondylitis, dysmenorrhea, post-operative pain, and a vari­

ety of ophthalmic diseases [3]. Besides, it has antimicrobial, lipid per­
Diclofenac (DCF), also known as 2-[(2,6-dichlorophenyl)amino] oxidation, and antitumor effects [4]. DCF targets for antineoplastic
phenyl-acetate, is a phenylacetic acid-class NSAID [1]. Diclofenac and activity include cell survival, tumor metabolism, and chemoresistance
diclofenac-containing drug products have been accepted in the USA for [5]. Because it binds to the cyclooxygenase (COX) enzymes necessary for
anti-inflammatory, analgesic, and antipyretic treatment and were mar­ the production of prostanoids from arachidonic acid, DCF is a powerful
keted in 1973. Alfred Sallman and Rudolf Pfister first created diclofenac inhibitor of prostaglandin synthesis. Here, the arachidonic acid cascade
sodium, and later diclofenac potassium, which has a quick onset of ac­ pathway-derived prostanoids include the inflammatory mediator’s
tion and immediate pain relief, was also produced [2]. It is most prostaglandin (PG)-E2, PGD2, PGF2, PGI2, and thromboxane (TXA2)
frequently recommended to relieve moderate to severe pain, including [6–8]. COX-1 and COX-2 are the two forms of COX protein whereas

* Corresponding author. Faculty of science Department of Chemistry University of Chittagong, Chittagong, 4331, Bangladesh.
E-mail address: monircu92@gmail.com (M. Uzzaman).

https://doi.org/10.1016/j.imu.2023.101159
Received 12 November 2022; Received in revised form 1 January 2023; Accepted 1 January 2023
Available online 2 January 2023
2352-9148/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Md.K. Hasan et al. Informatics in Medicine Unlocked 36 (2023) 101159

COX-1 is a “housekeeping” function that is responsible for physiological biological properties can be easily predicted without performing any
functions such as gastrointestinal (GI) tract protection, renal function costly experiment. The initial chemical file of Diclofenac (DCF) was
[9], maintenance, and platelet aggregation [10]. On the other hand, collected from an online chemical structure database named PubChem
cytokines and other inflammatory mediators can activate COX-2, which (PubChem CID: 3033). Structural modification of diclofenac and ge­
can be present in fibroblasts, macrophages, leukocytes, and synovial ometry optimization of all newly designed analogues was performed by
cells. COX-2 is also activated when inflammation occurs. Inhibiting utilizing the Gaussian 16.0 software package. Geometry optimization
COX-2 has been shown to have anti-inflammatory effects as well as was performed by using density functional theory (DFT), along with
antipyretic and analgesic effects [11]. B3LYP [22], and 6-31G (d, p) basis set in the gas phase. Further, TD-DFT
A study estimated that for human and veterinary purposes, 940 tons calculations were performed to investigate the electronic transition of
of DCFs are annually consumed all over the world [12]. Despite its these compounds. Frontier molecular orbital features: ϵHOMO (Highest
abundant clinical use, DCF exerts some crucial adverse effects like Occupied Molecular Orbital), and ϵLUMO (Lowest Unoccupied Molec­
gastrointestinal (GI) complications (bleeding, perforation, ulceration, ular Orbital) were calculated at the same level of theory. Subsequently,
enteropathy), cardiovascular problems (myocardial infarction, hyper­ the HOMO-LUMO energy gap, chemical hardness (η), chemical softness
tension, stroke, thrombotic events, heart failure, etc.), platelet inhibi­ (S), chemical potential (μ), electronegativity (χ ), and electrophilicity (ω)
tion, renal injury (acute tubular necrosis, renal papillary necrosis, were calculated using the Parr, and Pearson interpretation of DFT and
hypokalemia), as well as hepatotoxicity (hepatitis) and neurotoxicity Koopmans theorem by using the following equation [23].
[13–15]. Abdominal pain, mild to severe dyspeptic symptoms, hemor­
[εLUMO − εHOMO] 1
rhage, gastroduodenal ulcers, perforation, and nonspecific colitis are the Gap (ΔE) = [εLUMO − εHOMO]; η = ; S=
2 2η
common clinical features of upper GI tract injury [16]. These GI effects
are the result of COX-1 isoenzyme inhibition, causing the reduction of 2
[εLUMO + εHOMO] [εLUMO + εHOMO] μ
prostaglandin synthesis, which acts on gastric mucosa and gives a strong μ= ; χ= − ; ω=
2 2 2η
protective effect. This mechanism is also known as the prostaglandin
hypothesis. However, it is now recognized that GI damage and cellular
mitochondria impairment are dependent on NSAIDs (DCF) chemical 2.2. Molecular docking simulation, analysis, and visualization
structure and their molecular interaction ability with lipids [9]. Vulture
populations have dropped dramatically in India, Bangladesh, Pakistan, The protein structure (PDB ID:5F1A) of human cyclooxygenase-2
and Nepal as a result of people eating DCF-cared-for deceased animals [24] was collected in PDB forma from the online database protein
[17]. In 2006, India became the first nation in the world to outlaw the data bank (PDB) [25]. Hetero atoms, water molecules, and unwanted
production and use of DCF [18]. Additionally, Nepal, Pakistan, and chain were removed from the protein chain by utilizing PyMOL (Version
Bangladesh all restricted their use for veterinary purposes in 2008 and 1.7.4) software package and energy minimization of the protein struc­
2010 [19]. However, DCF is commercially produced in Spain and Italy ture were performed to remove bad contacts of the protein atoms uti­
for veterinary use and is exported to other EU nations. Because of this, lizing Swiss-PdbViewer (Version 4.1.0) software. Finally, using the
several well-known groups, like the Royal Society for the Protection of PyRx-Virtual Screening Tool (Version 0.8) followed by auto dock
Birds, Bird Life Europe, and the Vulture Conservation Foundation, are wizard, molecular docking studies were performed on these optimized
pushing for the veterinary use of diclofenac to be limited, like it is in drug structures against human prostaglandin synthase protein (5F1A),
India [20]. with the protein structure as the macromolecule and the optimized
So, the alternative to DCF is urgently needed to reduce the adverse compounds as the ligand [26]. Besides, flexible molecular docking was
effects. Our study aims to design new DCF derivatives for major adverse performed with a center grid box size of 64.83 Å, 76.42 Å, and 56.45 Å in
complications with potent medicinal actions. Moreover, more research x, y, and z-axis directions respectively, where the protein structure was
has been published yet to find out alternatives, but our study is fully covered by the grid box. The active site was visually examined
completely different from others because we only focus on suppressing using Biovia Drug Discovery Studio visualizer 2020, and the results were
the major side effects with some positive responses. Besides, this study is confirmed using Autodock Vina [27]. AutoDock Vina calculates a pre­
the extension of our previous diclofenac paper [21]. At present, struc­ cise and high-performance docking score for a specific ligand at a
tural modification is the best method to find new derivatives or ana­ binding site, as well as several orientations and conformations. Further,
logues of any drug. Besides, it is the easiest and cheapest way to achieve Accelrys Discovery Studio (Version 4.1) was used for performing the
proper target selectivity and exerts low side effects [21]. When their calculation of nonbonding interaction and to display and analyze the
chemical structure is modified, their physical, chemical, biological, docking results.
spectral, and ADMET properties are also significantly changed. In DCF,
the ‘COOH’ functional group is responsible for causing major adverse 2.3. Molecular dynamics simulation
complications. So, we remove the hydroxyl (OH) portion of COOH by
inserting 8 different functional groups at the R position of the DCF core The molecular dynamics simulations study was conducted in
structure. Insertion of these functional groups (CH3, OCH3, CH2NH2, YASARA dynamics [28] with the aid of the AMBER14 force field [29].
NH2, NHCOCH3, NHCONH2, Cl, CF3), into the entire derivatives, in­ The docked complexes were initially cleaned, and optimized and
dicates improved physicochemical, biological, and medicinal properties. hydrogen bonds were oriented. The TIP3P water solvations model was
Besides, the pass prediction data revealed that the potential candidate used with periodic boundary conditions [30]. The total systems were set
showed less adverse effect compared to parent DCF. Finally, we believe as 298 K temperature, pH 7.4, and 0.9% NaCl. The initial energy mini­
that this study will be useful in developing new potential DCF candidates mizations were conducted in the steepest gradient approached by
that are not ulcerogenic. simulated annealing methods (5000 cycles). The long-range electro­
static interactions were calculated by the Particle Mesh Ewald (PME)
2. Methods and materials methods with a cut-off radius of 8.0 Å [31–33]. The time step of the
simulations was set as 2.0fs. By following the Berendsen thermostat and
2.1. Computational details constant pressure the simulations were extended for 100ns [34]. The
simulation’s trajectories were saved after every 100ps and used to
The computational methodology is commonly practiced in the pro­ analyze the root mean square deviations, hydrogen bond, the radius of
cess of drug discovery to predict the drug-like properties of new chem­ gyrations, solvent accessible surface area, and root mean square
icals. Thermodynamical, molecular orbital, spectral, and other fluctuations.

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2.4. ADMET, PASS, and drug-likeness prediction 3.2. Molecular orbital analysis

ADMET properties such as absorption, distribution, metabolism, The frontier molecular orbitals, known as the highest occupied mo­
excretion, and toxicity are carries important positions in pharmaceutical lecular orbital (HOMO) and the lowest unoccupied molecular orbital
analysis. All such profiles of these compounds were investigated by (LUMO), determine the molecule’s interaction with other species [42].
using the AdmetSAR online server [35]. The frontier molecular orbitals are significant in electric and optical
properties, chemical reactions, and UV–Vis spectra [43]. The
3. Result and discussion HOMO-LUMO gap influences the values of chemical softness, hardness,
chemical potential, electrophilicity, and electronegativity. A greater
3.1. Thermodynamic analysis HOMO-LUMO gap suggests low chemical reactivity and strong kinetic
stability since electron addition to a high-lying LUMO and electron
Drug’s structural features including their enthalpy, free energy, extraction from a low-lying HOMO are both unfavorable [44]. A low
dipole moment, electrostatic potential, and binding properties can be HOMO-LUMO gap indicates less kinetic stability, and more chemical
drastically changed by making simple structural changes [36,37]. Gibb’s softness because the transition is favored with a lower HOMO-LUMO
free energy, Enthalpy, and electronic energy can be used to forecast the gap [21]. In the present analysis, DCF shows the HOMO-LUMO gap
thermodynamic and kinetic feasibility of a reaction, as well as the (4.95 eV) whereas, DCF-8 shows the lowest energy gap (3.93 eV) with
product’s stability [38]. The best predictor of the interaction of binding the highest softness (0.25eV) which displays higher chemical activity
partners is free energy, with negative values denoting spontaneous and polarizability than other compounds (Table 2). Lower
binding and interaction [39]. According to Table 1, the free energy of HOMO-LUMO gaps and higher chemical softness values are exhibited in
DCF is − 1665.505 Hartree whereas, DCF-7 exhibits the highest negative all of the DCF analogues compared to DCF.
value − 2049.942 Hartree because the Cl functional group is inserted to
the R position of the main structure. DCF-8, DCF-6, DCF-5, DCF-2, and
DCF-3 have comparatively higher free energy values which are 3.3. Molecular electrostatic potential analysis
− 1927.350, − 1814.370, − 1798.306, − 1704.850 and − 1684.953 Har­
tree due to the presence of CF3, NHCONH2, NHCOCH3, OCH3, CH2NH2 The molecular electrostatic potential (MEP) explains the electronic
functional group at the core structure’s R position. All lower to higher distribution and nuclear charge of the molecule in their adjacent space.
negative values indicate that these structures are gradually energeti­ It also provides information on the molecule’s partial charge, dipole
cally, and configurationally more stable. The polar nature of a molecule moment, electronegativity, and chemical reactivity [45,46]. Hydrogen
can be measured by the dipole moment, and a greater dipole moment bonding and the biological recognition process can be interpreted by the
can make a molecule more polar [40]. Elevated dipole moment can in­ MEP [47]. It also helps to predict the physicochemical properties of a
crease the binding affinity of non-bonding interaction in drug and re­ drug-like molecule and they perform as an H-bond donor and acceptor to
ceptor proteins complex and hydrogen bonding [41]. The dipole their receptor, respectively [48]. The deep red color, which is a site that
moment of DCF is 0.445 Debye whereas; DCF-6 shows the highest dipole is rich in electrons and is hence a favorable site for the electrophilic
moment 3.037 Debye hence, suggesting an increased binding affinity attack, represents the most negative regions. Whereas, the deep blue
with the receptor protein. color, which is electron-deficient and thus suitable for the nucleophilic
attack, represents the most positive areas. The color green represents
zero potential regions.
From the MEP map (Fig. 1), hydrogen atoms have the most positive
potentiality, whereas oxygen atoms have the highest negative

Table 1
Chemical structures, enthalpy, free energy (Hartree), and dipole moment (Debye) of DCF, and its newly designed analogues.

Name R Molecular formula Molecular weight Enthalpy Free energy Dipole moment

DCF OH C14H11Cl2NO2 296.149 − 1665.505 − 1665.569 0.445

DCF-1 CH3 C15H13Cl2NO 294.181 − 1629.556 − 1629.621 1.411
DCF-2 OCH3 C15H13Cl2NO2 310.18 − 1704.781 − 1704.850 1.106
DCF-3 CH2NH2 C15H14Cl2N2O 309.196 − 1684.884 − 1684.953 0.878
DCF-4 NH2 C14H12Cl2N2O 295.169 − 1645.627 − 1645.692 2.821
DCF-5 NHCOCH3 C16H14Cl2N2O2 337.206 − 1798.232 − 1798.306 2.628
DCF-6 NHCONH2 C15H13Cl2N3O2 338.194 − 1814.299 − 1814.370 3.037
DCF-7 Cl C14H10Cl3NO 314.599 − 2049.876 − 2049.942 2.929
DCF-8 CF3 C15H10Cl2F3NO 348.151 − 1927.279 − 1927.350 2.117

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Table 2
Energy (eV) of HOMO-LUMO, gap, hardness (η), softness (S), chemical potential (μ), electronegativity (χ ), and electrophilicity (ω) of DCF analogues.
Name ϵHOMO ϵLUMO GAP η S μ χ ω
DCF − 5.552 − 0.603 4.949 2.474 0.202 − 3.077 3.077 11.716
DCF-1 − 5.477 − 0.836 4.641 2.321 0.216 − 3.157 3.157 11.563
DCF-2 − 5.490 − 0.549 4.941 2.471 0.202 − 3.019 3.019 11.261
DCF-3 − 5.534 − 0.899 4.635 2.318 0.216 − 3.217 3.217 11.990
DCF-4 − 5.363 − 0.450 4.914 2.457 0.204 − 2.906 2.906 10.377
DCF-5 − 5.620 − 1.204 4.416 2.208 0.227 − 3.412 3.412 12.850
DCF-6 − 5.603 − 0.869 4.733 2.367 0.211 − 3.236 3.236 12.393
DCF-7 − 5.899 − 1.265 4.634 2.317 0.216 − 3.582 3.582 14.865
DCF-8 − 5.765 − 1.836 3.929 1.964 0.255 − 3.801 3.801 14.186

Fig. 1. Molecular electrostatic potential map of DCF analogues.

potentiality. In this present investigation, DCF possesses electrophilic this study. All the absorbance of the N–H functional group present in
potential values of − 0.1930 and + 0.1607 a.u. Due to the existence of DCF and all modified structures fluctuated and were found in the range
NH2 and NHCOCH3 functional groups in the R position of the core of higher frequency. The most significant deviation was observed (at
structure, DCF-4 and DCF-5 have the highest negative potentiality 3410 cm− 1) for N–H present in DCF-7.
(− 0.2313 a.u, deep red) whereas, DCF-8 and DCF-6 show maximum
positive potentiality (+0.2392 a.u and +0.2214 a.u, deep blue) due to 3.4.2. C–H vibrations
the presence of CF3 and NHCONH2 functional group respectively in the The IR band for C–H present in the benzene ring of all modified
R position of the core structure, which indicates the greatest possibility structure along with DCF were found in 3227 cm− 1. The calculated re­
of an electrophilic and nucleophilic attack on the target area. sults are also in good agreement with the literature values (3150-3050
cm− 1) [55].

3.4. Vibrational spectral analysis

3.4.3. C–– O vibration
The C–– O IR band present in the carboxylic acid functional group of
Spectroscopic technique, Infrared Spectroscopy (IR) is mostly used to
DCF is reported in the range between 1572 and 1394 cm− 1, while the
assure the functional groups present in different chemical compounds
calculated value for this functional group present in DCF and all its
and reveal the composition of that compounds as well [49]. In this
modified structures under investigation is found in the range of
present study, spectral characterization has been done and compared
1813–1688 cm− 1. The difference in the IR band is because of the pres­
with the experimental data of the mother compound DCF [50–52]. The
ence of the functional group in a different chemical environment that
FT-IR spectral band frequencies were recorded in the range of 4000–400
occurred due to the modification of the functional group of DCF.
cm− 1. All typical functional groups showed IR absorption in a higher
frequency than the experimental values and this is probably the pres­
3.4.4. C–
– C vibrations
ence of a basis set, neglect of vibrational anharmonicity, electron cor­
The ~866-632 cm− 1 band is assigned to the dichlorinated benzene
relation effects, and shallowness of potential energy surface [53].
ring (C–
– C) of DCF and the calculated scaled values of DCF and its
Therefore, all vibrational frequencies were scaled by a factor of 0.9627
modified compounds are found in the range 748–759 cm− 1 which is
for the basis set to improve the computed results [54]. Selected vibra­
completely in good agreement [50].
tional frequencies are listed (table: S1) and their corresponding spectra
are depicted (Fig. 2). A detailed description of the vibrational spectra of
selected functional groups is discussed in the following subsections. 3.5. UV–visible study

3.4.1. N–H vibrations To understand the nature of electronic transition within the mole­
The band for N–H (secondary amine) present in DCF was reported in cule, time-dependent density functional theory (TD-DFT) calculations
3240 cm− 1 and is quite lower than the theoretically calculated values in were performed for all molecules under investigation [56]. In this case,

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Md.K. Hasan et al. Informatics in Medicine Unlocked 36 (2023) 101159

the time-dependent (TD)-DFT-B3LYP/631G(d,p) method had been docked conformation based on the whole energy of the system [61].
employed to calculate the electronic transition spectra of all modified Docking imparts an important role to organize the positions, orienta­
structures along with DCF [57]. The absorption peaks (λmax’s), excita­ tions, and conformations of the 3D structure of ligands into macromol­
tion energies, oscillator strengths (f), and assignment of the transitions ecules and it is related to Computer-Aided Drug Design and Discovery
of all molecules were calculated and tabulated (Table S2). On the other [62]. In the ligand-protein complex, the stability of docked occurs as a
hand, UV–Vis’s spectra of all molecules were visualized in Fig. 2(b). In result of hydrogen bond and van Der Waals force [63]. Moreover, the
this current study, the maximum absorption wavelength of all molecules process of molecular docking resembles the lock and key method [64].
had observed in the range between 200 and 400 nm in the UV–Vis re­ In the current world, it is noted that molecular docking is a widely used
gion. For DCF-8, absorption maximum was observed at 384.45 nm at S0 technique in drug discovery [59]. Because, the program of docking is a
→S1 excited state with the configuration composition 0.698 (H→L), with virtual screening of structure-based design and it decreases the research
f = 0.0354 oscillator strength. On the other hand, In the calculation cost [59,65]. In molecular docking, the greater negative value represents
spectrum, the absorption band located at 279.09 nm (f = 0.0221) was the powerful bonding between ligands and receptors [21]. In our
assigned due to the transition from the H→L+2 molecular orbital of exploration of DCF and its analogues, almost all the compounds have
DCF-7. As DCF-8 showed absorption maxima at a longer wavelength, strongly bonded with 5F1A (Fig. 3 (a) and (b)). Additionally, those drugs
therefore it has the lowest energy and shows the most stable among all were well-fitted into the selecting proteins (5F1A) during the docking
molecules. At the same time, absorption maxima were observed for process and exerted the desired binding affinity (Table 3). Here, the
DCF-7 at the lowest wavelength, therefore it has the highest energy and docking analysis has preferred an excellent binding affinity of DCF-5
shows the lowest stability. The highest peak intensity was found for (− 8.6 kcal/mol), DCF-6 (− 8.6 kcal/mol), and DCF-8 (− 8.0 kcal/mol)
DCF-4, while a peak with the lowest intensity was observed for DCF-8 analogues among all of those compounds. However, only one compound
[58]. (DCF-2) has pretended slightly lower binding affinity than other
compounds.
Furthermore, non-bonding interactions determine how stable a drug
3.6. Docking and interactions analysis is within the target site and they are responsible for raising the ability
and changing the binding affinity [21]. So, non-bonding interactions
Molecular docking is employed as the computational investigation contribute a crucial role in the ligand-protein complex. There are some
that is provided to estimate the binding affinity of association between non-covalent interactions such as conventional hydrogen,
ligand-protein complex and it is a fundamental tool for drug design [59, carbon-hydrogen, and hydrophobic bonds are founded in inter­
60]. The main purpose of molecular docking is obtained to optimize connecting with 5F1A [21]. Here, hydrogen and hydrophobic bonds are
weak intermolecular interactions and they help to enhance the drug
efficacy on binding affinities of ligand-protein complex [66]. In addi­
tion, hydrogen and hydrophobic bonds work to stabilize energetically
favored ligands. Moreover, the hydrogen bond is performed when the
specificity of the ligand binds with the macromolecule [67]. A H-bond
contributes a great role in non-bonding interactions and it constitutes a
hydrogen bond donor and hydrogen bond acceptor which are denoted
by pink and green color respectively in Fig. 3(d). In the H-bond surface,
the H-bond donor defines where electron densities are fewer in the
electronegative atom while the H-bond acceptor contains more electron
densities in the electronegative atom [68]. Some amino acids (LEU391,
HIS386, HIS388, VAL447, and THR206) are interconnected with
H-bond. From this analysis, some selected nonbonding interactions of
DCF analogues have been visualized in Fig. 3(c). Most of the compounds
give conventional H-bonds which are treated with TYR385, ALA199,
TRP387, ASN382, HIS386, GLY45, ARG44, and THR206 amino acids.
Besides this, DCF-2, DCF-5, and DCF-6 provide carbon-hydrogen bonds
interacting with TRP387, HIS386, and HIS386 amino acids. Almost all
compounds have shown Pi-Alkyl bonds. In biological or medicinal
chemistry, halogen bonds have an essential impact to develop a new
design of materials [69]. Halogen (fluorine) bonds are noticed in DCF-8
which bonded with ALA199, ALA202, TYR385, and ALA202. Alkyl
bonds are showed in DCF-2, DCF-4, DCF-5 and DCF-6 which are asso­
ciated with LEU391, LEU390, VAL46, CYS47, PRO153, and VAL447
amino acids. Finally, only DCF-1 showed Amide-Pi Stacked bond with
ALA202 amino acid.

3.7. Molecular dynamic simulations

The molecular dynamics simulations were conducted to understand

the stable nature of the docked complexes. The root means square de­
viations of the complexes were analyzed to understand the stable con­
formations of the complexes. Fig. 4(a) indicates that the complexes had
an initial upper trend at the beginning of the simulations which indicates
the flexible nature of the complexes. The complexes were subsequently
stabilized after 20ns times. The DCF-8 complexes had higher RMSD
compared to the other complexes which define the overall less stability
Fig. 2. (a) FT-IR and (b) UV–Vis spectra of some selected compounds. of these complexes. However, all of the complexes had RMSD less than

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Fig. 3. (a) Docked conformer, (b) nonbonding interactions, and (c) hydrogen bond surface area of DCF-5, 6, and 8 with the receptor protein.

2.5 Å which indicates the complex’s stable nature. The solvent- effects [75]. However, for cardiac muscle, the human
accessible surface area of the complexes indicates the changes in pro­ ether-a-go-go-related gene (hERG) is required to open the potassium
tein surface area where the higher SASA relates with the expansions of channel. All of the drugs in this situation have non-inhibitory properties,
the surface area and lower SASA relates with the truncated nature of indicating that they are safe for the heart muscle. However, hERG gene
these complexes. Fig. 4(b) indicates that the complexes had stable na­ suppression may result in arrhythmia or lengthen the QT interval [76].
ture and exhibit a lower degree of fluctuations in SASA. The radius of the
gyrations profile of the complexes relates with the mobile nature of the
complexes where the higher Rg defines more flexibility and lower Rg 3.9. PASS and drug-likeness prediction
relates with the more stable nature. Fig. 4(c) indicates that the com­
plexes had stable nature in the Rg profile. PASS (Prediction of Activity Spectra for Substances) prediction de­
The hydrogen bond of a drug-protein complex plays an important termines the biological activities of different compounds by using the
role in determining the stable nature of the complexes whereas Fig. 4(d) PASS online server [77]. Depending on the study of structure-activity
indicates a lower degree of deviations in hydrogen bond patterning for relationships, the PASS prediction contains information on the biolog­
the complexes. The root means square fluctuations of the complexes ical activity of more than 300,000 compounds [78]. On the other hand,
indicate the flexible nature of the complexes across the amino acid this tool is arranged with 4000 biological activities of organic com­
residues. Fig. 4(e) indicates maximum residues from all complexes had pounds based on their molecular structural formulas, which are shown
RMSF less than 2.5 Å which indicates the complex’s stable nature. to have above 95% accuracy [78]. From Table 5, we notice that DCF and
its analogues have shown different values for different properties. Here,
almost all analogues have been exposed to the action of
3.8. ADMET analysis anti-inflammatory (the values vary from 0.576 to 0.656), antipyretic
(0.325–0.827), and analgesic (0.345–0.469) agents. Only DCF-7 lacks
Table 4 summarizes the results of the AdmetSAR online server’s analgesic activity. More importantly, DCF-6, DCF-7, and DCF-8 don’t
analysis of the ADMET profile, including the distribution, metabolism, cause hematuria (the presence of blood in urine). Besides this, DCF-1 to
excretion, and toxicity of DCF and its modified derivatives. From the DCF-8 have been exposed to a comparatively lower action of gastroin­
AdmetSAR calculation, all the compounds show positive results for testinal hemorrhage than DCF, and DCF-6 has the lowest action of
human intestinal absorption (HIA) and CACO-2 permeability. Greater gastrointestinal hemorrhage among all of the derivatives. Then, the
HIA denotes that these compounds have better absorption power in the analogues of DCF have also been exerted to reduce the action of necrosis
intestinal tract after oral administration [70]. All the drugs have a much (death of body tissue), hepatitis and an aphthous ulcer (canker sores)
greater affinity to pass through the blood-brain barrier via passive whereas DCF gives relatively higher activity of those properties. More­
diffusion or active transport mechanisms compared to the parent drug over, nephrotoxicity is reduced drastically, which is found in all DCF
DCF (+0.9541). In addition, CACO-2 cells simulate a range of trans­ analogues (reduced from 0.650 to 0.239). Furthermore, all newly
cellular pathways as well as the metabolic conversion of test chemicals modified analogues of DCF have decreased the hematotoxic effect
by expressing transporter proteins, phase II conjugation enzymes, and markedly compared to the parent compound (DCF). Therefore, it is
efflux proteins. All the derivatives pass the CACO-2 monolayer [71]. proved that these analogues give the activities of analgesic,
However, because of potential neurotoxicity and undesired pharmaco­ anti-inflammatory and antipyretic properties. From our investigational
logical effects, BBB penetration should be minimized for non-CNS drugs analysis, DCF analogues minimize the adverse reactions of the human
[72]. Moreover, all the derivatives are non-carcinogenic and exhibit body. To sum up, it can be stated that all new build-up candidates of DCF
category III oral toxicity, whereas DCF shows category II acute oral have performed better than the parent compound to abate the detri­
toxicity. So, from our study, it is clear that our predicted drugs are mental effects of DCF in the human body.
comparatively safer for oral administration than the parent drug [73]. Drug-likeness is used to evaluate the physicochemical properties of
Furthermore, our research shows that none of the substances are compounds in drug discovery and determine the uniformity within
P-glycoprotein inhibitors, although P-glycoprotein inhibition may pre­ compounds and drugs [79]. So, in the drug-likeness prediction, some
vent absorption, permeability, metabolism, as well as retention [74]. rules are included based on the highly developed machine learning
Herein, all the modified derivatives indicate lower median lethal dose methods and show an immense review in the research field [80]. Lip­
(LD50) values than DCF, which means that they have slightly harmful inski’s rule, “the Rule of five,” published in 1997, was the most

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Md.K. Hasan et al. Informatics in Medicine Unlocked 36 (2023) 101159

Table 3 Table 3 (continued )

Binding affinity and nonbonding interactions of all compounds. Name Binding Residue in Interaction type Bond
Name Binding Residue in Interaction type Bond affinity (kcal/ contact distance
affinity (kcal/ contact distance mol) (Å)
mol) (Å)
LEU391 Pi-Alkyl 5.30515
DCF − 7.7 TYR385 Conventional Hydrogen 3.07396 VAL444 Pi-Alkyl 5.01454
Bond VAL447 Pi-Alkyl 5.10398
ALA199 Conventional Hydrogen 2.13962 HIS388 Pi-Alkyl 4.47611
Bond
DCF- − 7.7 TYR385 Conventional Hydrogen 3.03760
HIS386 Pi-Pi Stacked 4.83026
7 Bond
LEU391 Pi-Alkyl 5.12166
GLN203 Conventional Hydrogen 2.76518
TYR385 Pi-Alkyl 5.34576
Bond
HIS386 Pi-Alkyl 3.52921
HIS386 Pi-Pi Stacked 4.72039
HIS388 Pi-Alkyl 4.33638
LEU391 Pi-Alkyl 5.26350
DCF- − 7.8 HIS386 Pi-Pi T-shaped 4.83758 HIS207 Pi-Alkyl 5.36305
1 HIS388 Pi-Pi T-shaped 5.01072 TYR385 Pi-Alkyl 5.33847
ALA202 Amide-Pi Stacked 4.23434 HIS386 Pi-Alkyl 3.49415
ALA202 Pi-Alkyl 4.53639 HIS388 Pi-Alkyl 4.45944
HIS207 Pi-Alkyl 4.61153
DCF- − 8.0 GLN203 Conventional Hydrogen 2.88753
HIS386 Pi-Alkyl 4.82248
8 Bond; Halogen (Fluorine)
DCF- − 7.6 TRP387 Conventional Hydrogen 2.87961 TRP387 Conventional Hydrogen 2.22708
2 Bond Bond
TRP387 Carbon Hydrogen Bond 2.63218 ALA199 Halogen (Fluorine) 3.50408
HIS207 Pi-Pi T-shaped 4.82822 ALA202 Halogen (Fluorine) 3.22800
HIS386 Pi-Pi T-shaped 4.89008 ALA202 Halogen (Fluorine) 3.62434
HIS388 Pi-Pi T-shaped 5.62134 TYR385 Halogen (Fluorine) 3.18493
LEU391 Alkyl 4.41571 HIS386 Pi-Pi T-shaped 5.09411
LEU390 Alkyl 4.86605 LEU391 Pi-Alkyl 5.25095
VAL444 Pi-Alkyl 5.19736 VAL447 Pi-Alkyl 5.06524
VAL447 Pi-Alkyl 4.71572 HIS207 Pi-Alkyl 4.70786
HIS207 Pi-Alkyl 4.99002 HIS386 Pi-Alkyl 3.70709
HIS388 Pi-Alkyl 4.51638 HIS388 Pi-Alkyl 4.52481

DCF- − 7.8 ASN382 Conventional Hydrogen 2.09187

3 Bond
well-informed rule that defined whether a molecule is orally active or
HIS386 Conventional Hydrogen 2.59892
Bond not [81]. In these five rules, if a molecule violates two or more rules, it
HIS207 Pi-Pi T-shaped 4.51734 will not be orally active [81]. From Table 6, all the analogues followed
ALA202 Pi-Alkyl 5.13822 the drug-likeness rule, like Lipinski et al. [82], Ghose et al. [83], Veber
HIS207 Pi-Alkyl 4.35023
et al. [84], Egan et al. [85], and Muegge et al. [86], and gave the
PHE210 Pi-Alkyl 5.31471
HIS388 Pi-Alkyl 4.65919
bioavailability score (0.55). On the contrary, DCF-1, DCF-7, and DCF-8
have shown one violation of different rules. The number of hydrogen
DCF- − 7.8 GLY45 Conventional Hydrogen 2.25057
bond donors and acceptors (known as a molecular descriptor) is used to
4 Bond
ARG44 Conventional Hydrogen 1.92783 determine the oral bioavailability of drug molecules [87]. Therefore,
Bond Drug’s membrane permeability and partition can be affected as a result
VAL46 Alkyl 3.86581 of too many hydrogen bond donors and acceptors [87]. Lipinski’s rule
CYS47 Alkyl 5.23990
states that poor absorption or membrane permeability of drug molecules
PRO153 Alkyl 4.89270
ARG44 Pi-Alkyl 4.94787
occurs when two or more criteria are met by the following consider­
LEU152 Pi-Alkyl 5.17638 ations: M.W. (molecular weight) > 500, calculated log P value > 5,
PRO153 Pi-Alkyl 5.15898 H-bond donors >5, and H-bond acceptors >10 [88]. Finally, our
CYS47 Pi-Alkyl 4.94441 investigation of the analogues of DCF has been performed to overcome
PRO153 Pi-Alkyl 4.15645
the poor absorption or permeation of drugs.
HIS39 Pi-Alkyl 4.83928
TYR130 Pi-Alkyl 5.36856
4. Conclusion
DCF- − 8.6 THR206 Conventional Hydrogen 3.00210
5 Bond
HIS386 Carbon Hydrogen Bond 3.55397 In summary, this investigation can be helpful in the development of
VAL447 Alkyl 5.41561 new compounds derived from structural modifications of diclofenac.
LEU391 Alkyl 4.19464 The addition of various functional groups in the core structure’s “R"
LEU391 Pi-Alkyl 5.48555
position improved its physicochemical, biological, and pharmacological
LEU391 Pi-Alkyl 5.31372
VAL444 Pi-Alkyl 5.02205 properties. From quantum calculations, different functional groups
VAL447 Pi-Alkyl 5.09007 increased the free energy of the parent drug (except DCF-1 and DCF-4)
HIS388 Pi-Alkyl 4.44221 and the dipole moment. Molecular orbital analysis discloses that all
DCF- − 8.6 TYR385 Conventional Hydrogen 2.76004 the DCF analogues have a lower HOMO-LUMO gap and higher chemical
6 Bond softness values than the parent drug, which has high chemical reactivity.
THR206 Conventional Hydrogen 2.68758 Vibrational and absorption spectral calculations represent their chemi­
Bond
cal existence. From the molecular docking simulation, most of the an­
HIS386 Carbon Hydrogen Bond 3.69083
HIS386 Pi-Donor Hydrogen Bond 2.92935 alogues exhibited better binding affinity than the parent drug, except for
VAL447 Alkyl 5.44783 DCF-2. According to molecular dynamics simulation analysis, all novel
LEU391 Alkyl 4.18237 analogues form stable complexes with the receptor protein (except DCF-
LEU391 Pi-Alkyl 5.38125
8). The pharmacokinetic result predicts, all newly designed analogues
will have better absorption power and much more affinity to pass the

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Md.K. Hasan et al. Informatics in Medicine Unlocked 36 (2023) 101159

Fig. 4. Result of 100 ns MD simulation of 5F1A in complex with DCF-2, DCF-5, DCF-6, and DCF-8 ligands (a) RMSD values of docked complexes from C-α atoms. The
structural changes of receptor protein by means of (b) SASA, (c) Rg, (d) number of hydrogen bonds formed, and (e) RMSF respectively.

Table 4
Pharmacokinetic parameters of all compounds.
Name BBB HIA C2P P-GI hERG inhibitor Carcinogens AOT RAT LD50 (mol/kg)

DCF +(0.9541) +(0.9548) +(0.8867) NI (0.9548) NI (0.8680) NC (0.6706) II 3.6447

DCF-1 +(0.9931) +(0.9968) +(0.8362) NI (0.8589) NI (0.7273) NC (0.5766) III 2.7018
DCF-2 +(0.9849) +(0.9876) +(0.8269) NI (0.9382) NI (0.8636) NC (0.7307) III 2.9845
DCF-3 +(0.9819) +(0.9906) +(0.6646) NI (0.7284) NI (0.6096) NC (0.5634) III 2.5471
DCF-4 +(0.9956) +(0.9681) +(0.6786) NI (0.9854) NI (0.7696) NC (0.5900) II 2.9132
DCF-5 +(0.9967) +(0.9706) +(0.6155) NI (0.9635) NI (0.7835) NC (0.5792) III 2.3350
DCF-6 +(0.9900) +(0.9314) +(0.5328) NI (0.9891) NI (0.8723) NC (0.7238) III 2.5044
DCF-7 +(0.9920) +(0.9874) +(0.8672) NI (0.9469) NI (0.8159) NC (0.6036) III 2.5744
DCF-8 +(0.9952) +(0.9968) +(0.7649) NI (0.7985) NI (0.6760) NC (0.6135) III 2.7732

BBB= Blood brain barrier, HIA= Human intestinal absorption, P-GI= P-glycoprotein inhibitor, AOT = Acute oral toxicity, RAT = Rat acute toxicity, I= Inhibitor, NI=
Non inhibitor, NC= Noncarcinogen.

blood-brain barrier via passive diffusion or active transport mechanisms helpful to design the potential drug candidate for better medicinal
compared to the parent drug. Furthermore, all the analogues are non- efficacy.
carcinogenic and less toxic. All of the modified drugs have non-
inhibitory properties, indicating that they are safe for the heart mus­ Funding
cle. Biological activities and drug-likeness indicate that all the analogues
of DCF have been exposed to a comparatively lower action on gastro­ This research not received any fund.
intestinal hemorrhage than DCF, and exhibit antipyretic, analgesic, and
anti-inflammatory actions. All analogues have a good oral bioavail­ Declaration of competing interest
ability score and are performed to overcome the poor absorption or
permeation of drugs. Based on the above investigation, this study can be The authors declare that they have no known competing financial

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Md.K. Hasan et al. Informatics in Medicine Unlocked 36 (2023) 101159

Table 5
Predicted biological activity of all DCF analogues.
Name Analgesic Anti- Antipyretic Gastrointestinal Necrosis Hepatitis Hematuria Aphthous Nephrotoxic Hematotoxic
Inflammatory hemorrhage ulcer

DCF 0.469 0.656 0.827 0.966 0.798 0.886 0.639 0.733 0.650 0.717
DCF- 0.484 0.651 0.578 0.893 0.671 0.761 0.447 0.560 0.460 0.602
1
DCF- 0.516 0.778 0.709 0.941 0.792 0.857 0.574 0.593 0.579 0.635
2
DCF- 0.549 0.458 0.348 0.797 0.624 0.676 0.383 0.485 0.385 0.471
3
DCF- 0.555 0.598 0.621 0.844 0.567 0.790 0.307 0.578 0.575 0.614
4
DCF- 0.520 0.537 0.562 0.833 0.523 0.711 0.247 0.487 0.434 0.462
5
DCF- 0.453 0.430 0.356 0.756 0.446 0.532 – 0.437 0.266 0.291
6
DCF- – 0.283 0.270 0.864 0.468 0.500 – 0.445 0.239 0.260
7
DCF- 0.345 0.576 0.325 0.846 0.617 0.671 – 0.473 0.481 0.384
8

Table 6
Drug likeness parameters of some DCF analogues.
Drug Lipinski Ghose Veber Egan Muegge Bioavailability Number of H-Bond Number of H-Bond
(Violation) Score donor acceptor

DCF Y (0) Y Y Y Y 0.85 2 2

DCF- Y(1); Y Y Y Y 0.55 1 1
1 MLOGP>4.15
DCF- Y(0) Y Y Y Y 0.55 1 2
2
DCF- Y(0) Y Y Y Y 0.55 2 2
3
DCF- Y(0) Y Y Y Y 0.55 2 1
4
DCF- Y(0) Y Y Y Y 0.55 2 2
5
DCF- Y(0) Y Y Y Y 0.55 3 2
6
DCF- Y(1); Y Y Y N(1); 0.55 1 1
7 MLOGP>4.15 XLOGP3>5
DCF- Y(1); N(1); Y N(1); N(1); 0.55 1 4
8 MLOGP>4.15 WLOGP>5.6 WLOGP>5.88 XLOGP3>5

Y= Yes, N= NO.

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