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ORIGINAL PAPER
Investigation of the reactivity properties of a thiourea derivative
with anticancer activity by DFT and MD simulations
Y. Sheena Mary
1
&Y. Shyma Mary
1
&Anna Bielenica
2
&Stevan Armaković
3
&Sanja J. Armaković
4
&
Vivek Chandramohan
5
&Manjunath Dammalli
5
Received: 6 January 2021 /Accepted: 23 June 2021
#The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021
Abstract
Spectroscopic analysis of 1-(2-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (FPTT) is reported. Experimental and theo-
retical analyses of FPTT, with molecular dynamics (MD) simulations, are reported for finding different parameters like identi-
fication of suitable excipients, interactions with water, and sensitivity towards autoxidation. Molecular dynamics and docking
show that FPTT can act as a potential inhibitor for new drug. Additionally, local reactivity, interactivity with water, and
compatibility of FPTT molecule with frequently used excipients have been studied by combined application of density functional
theory (DFT) and MD simulations. Analysis of local reactivity has been performed based on selected fundamental quantum-
molecular descriptors, while interactivity with water was studied by calculations of radial distribution functions (RDFs).
Compatibility with excipients has been assessed through calculations of solubility parameters, applying MD simulations.
Keywords DFT .Thiourea .MD simulations .Docking .NLO
Introduction
Thiourea derivatives have diverse biological activities, like
antibacterial and anticancer activities, and they have a high
impact on the central nervous system of rodents [1–12].
Among thioureas, molecules incorporating
3-(trifluoromethyl)phenyl moiety are known for their strong
inhibitory effect on Gram-positive pathogens [1]. Their poten-
cy was noticeable towards both planktonic and biofilm-
forming structures of staphylococcal species [13,14].
Thiourea-derived connections exert also cytotoxicity against
different cell line tissues [15,16], as well as the panel of
viruses [17–22]. Additionally, thiourea compounds are exten-
sively used for coordination complexes with metal ions
[23–25] or cyclic derivatives such as tetrazoles [26]thatcould
serve as medicinal agents. Thiourea structures are an impor-
tant bioactive substructure in various bio-molecules having
various biological activities [27]. In pharmaceutical chemis-
try, the thiourea skeleton plays a significant role. Derivatives
of thiourea demonstrated strong cytotoxic activity against dif-
ferent cancer cells [28–31]. These compounds’desirable in-
hibitory activity against different inhibitors plays a key role in
the death of cancer cells [29–31]. In coordination chemistry,
thiourea behaves as a flexible ligand because it can coordinate
with a wide range of metal centers. Thiourea’s applicability
has also been successfully applied to its use as starting precur-
sors in synthetic chemistry and the design of practical gas
adsorption materials [32–34]. The emphasis of several review
papers remained based on outstanding biological applications
and efficiency of the thiourea class of compounds [35–37].
Synthesis and evaluation of new derivatives of thiourea as
antitumor and anti-angiogenic agents have recently been pub-
lished [38]. Many spectroscopic studies of thiourea deriva-
tives have been reported by the author’s community
[39–42]. Molecular modeling techniques, especially the ones
based on quantum mechanics and force fields, are very
*Y. Sheena Mary
marysheena2018@rediffmail.com
1
Thushara, Neethinagar-64, Kollam, Kerala, India
2
Department of Biochemistry, Medical University of Warsaw,
02-097 Warszawa, Poland
3
Faculty of Sciences, Department of Physics, University of Novi Sad,
Trg D. Obradovića 4, Novi Sad 21000, Serbia
4
Faculty of Sciences, Department of Chemistry, Biochemistry and
Environmental Protection, University of Novi Sad, Trg D.
Obradovića 3, Novi Sad 21000, Serbia
5
Department of Biotechnology, Siddaganga Institute of Technology,
Tumakuru, Karnataka 572103, India
Journal of Molecular Modeling (2021) 27:217
https://doi.org/10.1007/s00894-021-04835-9
important tools for the initial investigation of newly synthe-
sized molecules. Computational experiments have proven to
be able to successfully predict local reactivity properties of the
middle-sized organic molecules and in that way provide
deeper insights into the underlying mechanism involving
new molecules [43–46]. In this work, the combination of
quantum mechanical and classical (force field–based) calcu-
lations has been used, to predict and understand reactivity and
selected spectroscopic properties of FPTT molecule. In the
present research, experimental and theoretical analysis of
FPTT, with MD simulations, is reported for finding different
parameters like, identification of suitable excipients, interac-
tions with water, and sensitivity towards autoxidation.
Experimental details
Synthesis of FPTT and spectral measurements (Figures S1
and S2) is as in literature [1,6,39,40]. A solution of
3-(trifluoromethyl)aniline (0.0031 mol, 0.50 g) in dried aceto-
nitrile (10 mL) was treated with 2-fluorophenylisothiocyanate
(0.0031 mol), and the mixture was stirred at room temperature
for 12 h. Then the solvent was removed on a rotary evapora-
tor. The organic residue was purified by column chromatog-
raphy (chloroform).
NMR images (
1
Hand
13
C) for FPTT were recorded on a
500 MHz NMR spectrometer.
1
HNMRδ: 10.14 (s, 1H, NH),
9.71 (s, 1H, NH), 7.98 (s, 1H), 7.77 (d, 1H), 7.60–7.53 (m,
2H), 7.46 (d, 1H), and 7.29–7.15 (m, 3H).
13
CNMRδ:180.79
(C=S), 156.39, 140.29 (C2), 129.52 (C6), 128.95 (C4),
128.62 (C11), 127.63 (C16), 127.27 (C1), 126.62 (C14),
124.24 (C15), 122.01 (C18), 120.72 (C3), 119.71 (C5), and
116.01 (C13). HRMS (ESI) calc. [M –H]
–
: 313.0422, found:
313.0416.
Computational details
DFT/MO-5/6-311++G(d,p) is utilized for calculations of
wavenumbers by Gaussian09 and Gaussview 5.0 [47–52].
Frequency calculation–ensured optimized geometry
(Figure 1) corresponds to a global minimum. Quantum me-
chanics and force field calculations in this research have been
performed using the Schrodinger Suite 2020-4 (SMSS). When
the SMSS package was used, a Jaguar [53–55] and Desmond
[56,57] program was used for DFT and molecular dynamics.
The main GUI of SMSS, Maestro [58], was used for input/
output files. DFT calculations with Jaguar program have been
performed with B3LYP exchange-correlation functional, to-
gether with 6-31G(d,p) and 6-311G(d,p) basis sets [47,
59–61]. Single point energy calculations with the Jaguar pro-
gram were used for obtaining information on molecular elec-
trostatic potential (MEP) and average local ionization energy
(ALIE) descriptors. Bond dissociation for the hydrogen ab-
straction has been performed with B3LYP/6-31G(d,p) level
of theory. MD is a modeling method used to study the con-
formational rearrangement of molecules and their interactions
with other molecular species in many environments.
Regarding force field–based calculations, MD simulations
have been performed by using OPLS3e force field [62–65],
and for these simulations, the simulation time was set to 10 ns,
while other parameters included a temperature of 300 K, nor-
mal pressure, and cutoff radius of 10 Å. In all MD simulations,
the solvent was treated by a simple point charge (SPC) model
[66]. MD simulations were used for understanding the inter-
actions of FPTT with water and to obtain the solubility param-
eter. Further details on these calculations are provided in the
corresponding chapters.
MD simulation of the PDBs, 2PSQ, 5AEP, and 2V3Q with
FPTT is done by using GROMOS 53A6 force field of
GROMACS simulation package 1–2. The molecular dynam-
ics parameters and methods were followed as described earli-
er, and the 50 ns simulation time was carried in a cube box of
size 7.2 × 11 × 7.2 nm. The RMSD of the backbone was ana-
lyzed in GROMACS. The MMPBSA method gives binding
free energy (ΔG binding) of the ligand molecules with target
proteins over simulation time. The last 20 ns was subjected to
MMPBSA analysis [67–75]. Finally, to theoretically confirm
the potential of the title molecule in terms of biological activ-
ity, we have performed molecular docking study with the
appropriate proteins with the AutoDock-Vina software [76,
77].
Results and discussion
Geometrical parameters
The 1,3- and 1,2-disubstituted phenyl rings are termed as R1
and R2. C-C lengths rings of FPTT (Table S1) are 1.4041–
1.3922Ǻ(R1) and 1.4050–1.3802Ǻ(R2) [78]. The NH bond
lengths in the present case are 1.0110Ǻand 1.0134Ǻ[79].
C
16
-F
17
length is 1.3630Ǻ,andCF
3
lengths in the present case
are 1.3526, 1.3504, and 1.3505Ǻ[80,81]. The CCF and FCF
angles in the CF
3
group are 111.4, 111.9, and 111.6° and
106.9, 107.1, and 107.6°, respectively [82]. For FPTT, CN
lengths are 1.4137, 1.3815, 1.3624Ǻ, and 1.4069Ǻ[82]and
C-S is 1.6792Ǻ[79].
IR and Raman spectra
The υCF (Table 1) is normally at 1270–1100 cm
−1
[83]and
for FPTT, potential energy distribution (PED) analysis gives
the υCF at 1198 cm
−1
with 37% PED and experimentally
bands are at 1209 cm
−1
[84,85]. The CF
3
vibrational modes
for FPTT are at 1178, 1161, and 1129 cm
−1
(IR); 1168, 1156,
217 Page 2 of 14 J Mol Model (2021) 27:217
and 1133 cm
−1
(Raman); and 1173, 1155, and 1121 cm
−1
(DFT) [81,86]. PED gives 38, 65, and 41% for theoretical
υCF
3
, 1173, 1155, and 1121 cm
−1
with high IR intensities.
δCF
3
modes for FPTT are observed at 623, 558 cm
−1
(IR),
558, 368, and 270 cm
−1
(Raman) and assigned at 623, 569,
476, 376, 318, and 270 cm
−1
(DFT) [81].
υNH are assigned at 3203 cm
−1
(IR), 3212 cm
−1
(Raman),
and at 3507 and 3458 cm
−1
(DFT) [86]. For υNH modes, the
PED value is around 100% with an IR intensity 59.38 and
80.55 and Raman activity 162.97 and 181.95. The δNH
modes are at 1544, 1492, and 591 cm
−1
(IR); 1544, 1492,
636, and 588 cm
−1
(Raman); and 1529, 1478, 642, and
590 cm
−1
(DFT) with PEDs around 35%. For FPTT, the band
at 724 cm
−1
(IR), 726 cm
−1
(Raman), and 729 cm
−1
(DFT) is
assigned as υC=S mode [83,86,87] and reported modes are at
847 and 908 cm
−1
[88]. Bands at 1267 and 1178 cm
−1
(IR);
1345, 1242, and 1168 cm
−1
(Raman); and 1341, 1268, 1232,
and 1173 cm
−1
(DFT) are the υCN of FPTT [79].
Bands at 3135 and 3078 cm
−1
(IR) and at 3130 and
3086 cm
−1
(Raman) are the υCH modes of FPTT.
Theoretical values are at 3095, 3091, 3079, and 3074 cm
−1
for R1 and 3139, 3104, 3102, and 3089 cm
−1
for R2 rings
[86]. The bands at 1600 and 1318 cm
−1
(IR); 1607, 1465, and
1311 cm
−1
(Raman); 1610–1319 cm
−1
(DFT) and 1460 cm
−1
(IR); and 1593, 1447, 1345, and 1311 cm
−1
(Raman), in the
range 1617–1306 cm
−1
(DFT) are the ring υCC modes of R1
and R2 [86]. The ring breathing mode for FPTT is assigned at
964 and 1066 cm
−1
theoretically [89–92]. For FPTT, δCH is
at 1284, 1267, 1061, and 1026 cm
−1
(IR) and at 1285, 1087,
1070, and 1025 cm
−1
(Raman). DFT values are at 1299–
1054 cm
−1
and 1262–1017 cm
−1
ranges for R1 and R2 [86].
The γCH modes of FPTT are at 889 cm
−1
(IR); 959, 889, and
785 cm
−1
(Raman); and 954, 894, 885, and 778 cm
−1
(DFT)
and 750 cm
−1
(IR); 750 cm
−1
(Raman); and 942, 906, 830, and
748 cm
−1
(DFT) for rings R1 and R2.
Aromatic protons have chemical shifts (ppm) in the range
7.54 to 7.88 for phenyl ring R1 and 6.97 to 8.81 to the phenyl
ring R2 theoretically. For the NH groups, the shifts are 6.94
and 6.92 theoretically which shows deviations from experi-
mental results, 10.14 and 9.72. For the C8 atom, the chemical
shift is 177.65 theoretically, while the experimental result is
180.79. The carbon atoms in the ring R1 show chemical shifts
in the range 122.23 to 129.14, and for R2, the shifts are 116.80
to 153.77 theoretically. C16 and C18 show the highest shifts
of 153.77 and 132.90 due to the presence of fluorine atoms,
and the corresponding experimental values are 156.40 and
132.90. The deviations of experimental and theoretical results
are due to the following: theoretical calculations are in the
gaseous phase, while experimental results belong to the solid
phase.
NBO, chemical descriptors, and NLO properties
Important interactions from NBO analysis [93,94](TablesS2
and S3, energy in kcal/mol) are C12-C13 →BD*(C11-C16,
C14-C15) (21.14, 21.13), C11-C16 →BD*(C12-C13, C15-
C14) (18.31, 19.21), C15-C14 →BD*(C12-C13, C11-C16)
(19.26, 21.36), C2-C1 →BD*(C6-C5, C4-C3) (19.15,
20.35), C6-C5 →BD*(C2-C1, C4-C3) (21.39, 21.31), C4-
C3 →BD*(C5-C1, C6-C5) (19.75, 20.05), N9 →
BD*(C11-C16, C8-S10) (23.23, 65.94), S10 →BD*(N9-
C8, C8-N7) (12.09, 10.26), N7 →BD*(C8-S10, C2-C1)
(66.58, 16.35), F19 →BD*(C18-F21, C18-F20) (11.83,
12.21), F21 →BD*(C18-F19, C18-F20) (10.55, 13.05),
Fig. 1 Optimized geometry of
FPTT
JMolModel (2021) 27:217 Page 3 of 14 217
Table 1 Vibrational assignments of FPTT
MO-5/6-311++G(d,p) IR υ(cm
−1
)Ramanυ(cm
−1
) Assignments
a
υ(cm
-1
) IR intensity Raman activity
3507 59.38 162.97 υNH(100)
3458 80.55 181.95 3203 3212 υNH(99)
3139 8.66 48.79 3135 3130 υCHR2(98)
3104 4.27 180.26 υCHR2(99)
3102 8.07 218.73 υCHR2(96)
3095 4.21 46.24 υCHR1(99)
3091 1.19 54.56 υCHR1(99)
3089 18.69 141.12 3086 υCHR2(99)
3079 5.88 46.81 3078 υCHR1(100)
3074 2.64 67.83 υCHR1(95)
1617 74.80 322.82 υR2(61)
1610 26.65 97.73 1600 1607 υR1(63), δCHR1(16)
1593 55.38 37.12 1593 υR2(59), δNH(13)
1588 7.50 76.87 υR1(64), δCHR1(20)
1529 580.88 60.50 1544 1544 δNH(39), υR2(12), υCN(18)
1478 171.64 64.23 1492 1492 δNH(35)
1466 27.51 18.29 1465 δCHR1(18), R1(45)
1458 289.28 30.60 1460 δNH(12), υR2(41), δCHR2(20)
1430 34.00 19.46 1447 δCHR2(30), υR2(55)
1405 92.28 3.61 υR1(28), δCHR1(19), υCN(12),δNH(10)
1341 218.60 56.89 1345 υCN(37), υR2(30)
1319 15.49 11.42 1318 υR1(69), δCHR1(17)
1306 625.97 78.05 1311 υR2(35)
1299 54.36 5.82 1284 1285 υCC(25), δCHR1(27)
1268 59.42 4.12 1267 δCHR1(23), υCN(44)
1262 6.26 145.45 1267 δCHR2(46), υCN(14)
1232 23.06 24.18 1242 δCHR2(19), υCN(41), υCF(11), υR2(16)
1198 174.23 10.57 1209 1209 υCF(37), δNH(13), δCHR1(10)
1173 201.00 47.07 1178 1168 υCN(39), υCF(38), δCHR1(10)
1155 231.07 0.64 1161 1156 υCF(65)
1143 3.93 7.11 δCHR1(73), υR1(14)
1141 109.29 5.89 υCF(36), δCHR2(19)
1121 8.70 16.02 1129 1133 υCF(41), δCHR2(15), υCF3(11)
1120 295.28 2.44 δCHR2(49)
1079 31.24 2.57 1087 δCHR1(34), υR1(34)
1066 8.83 1.81 1061 1070 δCHR2(40), υR2(46)
1054 75.36 4.88 υR1(35), υCF(15), δCHR1(29)
1017 14.13 36.09 1026 1025 υR2(13), δCHR2(62)
964 1.46 74.02 961 968 δR1(33), υR1(56)
954 0.66 0.89 959 γCHR1(86)
942 0.24 0.33 γCHR2(82), τR2(11)
919 7.59 2.74 926 916 δR2(17), υCS(15)
906 3.10 0.18 γCHR2(87)
894 2.39 2.32 γCHR1(85)
885 21.75 0.86 889 889 γCHR1(48), τR1(14)
860 13.42 1.76 866 865 γCHR1(39)
830 0.15 0.38 γCHR2(75), τR2(11)
217 Page 4 of 14 J Mol Model (2021) 27:217
F20 →BD*(C18-F19, C18-F21)(10.35, 13.12), and F17 →
BD*(C11-C16) (18.94).
The first-order hyperpolarizability of FPTT is 2.333 ×
10
−30
which is 18 times that of urea and the second-order is
−16.688 × 10
−37
esu and polarizability is 2.153 × 10
−23
[95,
96]. The FMO (Figure 2)-associated molecular properties
are energy gap (2.742 eV), ionization potential (7.326 eV),
electron affinity (4.583 eV), chemical potential,
Table 1 (continued)
MO-5/6-311++G(d,p) IR υ(cm
−1
)Ramanυ(cm
−1
) Assignments
a
υ(cm
-1
) IR intensity Raman activity
791 24.51 21.85 802 797 δR2(37), υCF(19), υR2(12)
778 19.43 0.58 785 γCHR1(62), τR1(16)
748 2.38 11.43 750 750 γCHR2(90)
736 4.42 24.13 δNH(16), δR1(12)
729 74.61 0.25 724 726 υCS(34), δNH(14), δCN(14)
705 3.05 1.17 τR2(59), γCF(17), γCN(16)
687 24.69 0.93 696 τR1(62), γCHR1(29)
661 30.12 3.27 657 657 υCS(10), υCN(10)
642 7.64 2.20 636 γNH(35), γCS(28)
623 15.66 4.29 623 δR1(36), δCF3(35)
619 13.84 4.39 δR2(25), δR1(34)
590 13.40 4.04 591 588 δR1(47), γNH(31)
571 11.01 0.23 γCS(70)
569 1.73 1.31 558 558 δCF3(49)
539 0.20 0.37 541 τR2(60), γCN(14), γCF(13)
532 2.76 4.02 δR2(37), δNH(13), δCF3(13)
512 9.24 0.44 510 510 δCF3(13), δR2(25), τR1(10)
495 1.37 0.37 τNH(35), τCN(26), γNH(25)
476 114.33 42.63 τR1(15), δCF(13), δCF3(36), γCN(12)
443 6.99 0.79 446 446 τR1(51), γCN(10), δCF3(13)
439 0.98 2.62 τR2(44), γCF(21), γCN(14)
435 11.83 0.35 428 δCF(25), τR2(15), δCN(15)
381 1.29 0.39 368 δCF3(45), δCS(11), δCF(10)
339 5.03 1.17 335 δR1(28), δCF3(18)
324 0.42 7.34 δCN(17), δCS(16), τR1(10)
318 3.39 2.03 τR1(43), δCF3(24)
289 0.66 1.35 δR2(23), γCF(18), γCN(13), τR2(11)
270 1.30 4.90 270 δCN(19), δCF3(28), τR1(12)
219 2.35 2.31 τR1(28)
217 1.34 3.28 212 δCS(43), δCN(14), δNH(10), δCF3(10)
196 1.19 2.19 198 τR2(49), γNH(21)
154 1.70 1.01 150 δCN(16), δCC(15), τR2(11), δNH(16)
141 3.40 4.66 136 γCC(20), τCN(27), δNH(10)
122 2.07 4.58 118 γCC(31), δCF3(14), τCN(11), δCC(10)
85 1.85 1.30 90 γNH(28), τCN(12), τCS(10), τR2(10)
48 1.05 3.23 γNH(30), τNH(30), τCS(18)
32 0.99 3.29 τNH(47), γNH(36)
17 1.00 3.17 τCF3(76), δCC(13)
13 0.14 0.39 τNH(52), τCN(24), τCS(10)
11 0.58 1.90 τCN(61), τNH(25)
a
υ, stretching; δ, in-plane deformation; γ, out-of-plane deformation; τ, torsion
JMolModel (2021) 27:217 Page 5 of 14 217
(−5.954 eV), hardness (1.371 eV), and electrophilicity index
(12.929 eV). FPTT has an extremely high electrophilicity in-
dex value indicating bioactivity [97–99].
MEP and ALIE surfaces
Among many descriptors that are frequently used for the un-
derstanding of the local reactivity properties of organic mole-
cules, MEP and ALIE are certainly some of the most impor-
tant. Owing to their relation with the fundamental quantity in
the DFT approach and electron density, these descriptors are
the most frequently employed in computational studies to ex-
plain the local reactivity properties of studied molecules.
MEP descriptor is important because it gives information
about the charge distribution, allowing one to identify whether
effects of nuclei or electrons are dominant at points around the
molecule. Thanks to this, the MEP descriptor indicates which
parts of the molecule are sensitive to interactions with other
molecules.The importance of the ALIE descriptor is due to its
ability to show molecular sites in which the least amount of
energy is required for the removal of an electron, and therefore
for the ionization. Thanks to this, the ALIE descriptor indi-
cates which parts of the molecule are sensitive to electrophilic
Fig. 2 HOMO-LUMO plots of
FPTT
217 Page 6 of 14 J Mol Model (2021) 27:217
attacks. The importance and usefulness of these descriptors
have been indicated in many papers [100–103].
For visualization in the case of MEP and ALIE descriptors,
the best solution is to map their values to electron density
surface, thanks to which one obtains so-called MEP and
ALIE surfaces (Figure 3). According to Figure 3, the most
reactive atom of all is the sulfur atom. This atom is character-
ized by the lowest MEP (−33 kcal/mol) and ALIE (155 kcal/
mol) values, meaning that it is the most reactive with the other
positively charged molecular species and that it is the most
sensitive towards electrophilic attacks. The highest MEP
values (41 kcal/mol) are for hydrogen belonging to the ben-
zene ring, while the highest ALIE values (382 kcal/mol) are
for chlorine.
Sensitivity towards autoxidation
One of the greatest concerns during the development of new
drugs is the potential formation of genotoxic impurities, due to
the sensitivity of active components to the autoxidation mech-
anism [104,105]. Active components might have great bio-
logical activities; however, if they are sensitive to this mech-
anism, the whole project regarding the development of new
pharmaceutical products might be unsuccessful.
From the experimental standpoint, determining the sensi-
tivity of the drug candidate towards this mechanism might be
very challenging. Therefore, it is imperative to search for the-
oretical means of how to predict the sensitivity of a molecule
towards autoxidation. Luckily, it has been established that
hydrogen-bond dissociation energy (H-BDE) is related to this
important mechanism and that values of this parameter in the
range between 70 and 85 kcal/mol [106,107]mostprobably
indicate that the studied molecule is sensitive towards autox-
idation. Values 85–90 kcal/mol might indicate low sensitivity
towards autoxidation, but in such cases, other parameters must
also be taken into account. All H-BDE values for the FPTT
molecule have been summarized in Figure 4.
H-BDE results presented (Figure 4) indicate that it is rea-
sonable to expect that FPTT is highly stable towards the
autoxidation mechanism. Of all calculated H-BDE values, on-
ly two of them are lower than 112 kcal/mol. The two lowest
values have been calculated for hydrogen connected to nitro-
gen; however, both of these values are higher than 90 kcal/
mol, indicating that FPTT should be highly stable concerning
the autoxidation mechanism.
Interactions with water
Thanks to the MD simulations, the interaction of FPTT with
water was studied to identify atoms with relatively significant
interactions with water molecules. This has been obtained by
calculations of RDF, once the trajectories of all particles have
been collected. RDFs have been calculated concerning the
distance between the observed atom and oxygen of the water
molecules. RDFs that can be considered relatively important
are summarized in Figure 5(Figure S3 shows the formed
noncovalent interactions between FPTT and water as obtained
by DFT calculations). Molecules illustrated in ball and stick
representation indicate water molecules with which our inves-
tigated molecule has formed noncovalent interactions, in that
particular frame, according to the DFT calculations. Other
water molecules surrounding the studied molecule have been
illustrated in wire representation. Part of the MD frame pre-
sented in Figure S3 indicates the importance of S atoms; as in
this particular case, it formed noncovalent interactions with
three water molecules. Results that can be seen in Figure 5
show that it is expected for the FPTT molecule to be highly
stable in water. Namely, of all the calculated RDFs, only the
presented ones are having relatively sharp profiles, indicating
relatively significant interactions with water. However, a clos-
er analysis of these RDFs indicates that higher g(r) values are
located at high distances, showing that water molecules are
clustering at a high distance from the FPTT molecule.
Namely, all of these higher g(r) values are located at distances
much higher than 2 Å. The closed distance has been calculated
for atom S10 (around 3.7 Å). Carbon atom C6 is having a
similar profile whose maximal g(r) value is located at a slight-
ly higher distance. Maximal g(r) value is the highest in the
Fig. 3 MEP and ALIE surfaces of
FPTT molecule, expressed in
kcal/mol
JMolModel (2021) 27:217 Page 7 of 14 217
case of the carbon atom C18; it is also located at the highest
distance of more than 4 Å.
Identification of suitable excipients
Combining active components, possessing representative bio-
chemical properties, with excipients is an important approach
to improve their physical properties and enable practical ap-
plications. Namely, when it comes to the newly developed
active components, it is frequently necessary to improve their
stabilization, solubility, delivery properties, etc., and for these
purposes, substances known as excipients are used. The num-
ber of substances that can be applied as excipients is high, and
it might be time-consuming to select the excipient which is
compatible with the active component. Therefore, it is of in-
dustrial interest to identify computational methods that would
allow suitable choices of excipients for newly developed ac-
tive pharmaceutical components. In these regards, it has been
established that active components and excipients are compat-
ible if they possess similar values of solubility parameter
[108–110]. On the other side, it is meaningful that the solu-
bility parameter can be calculated computationally, via MD
Fig. 4 H-BDE values in case of
FPTT molecule, expressed in
kcal/mol
Fig. 5 Selected RDFs of FPTT
molecule
217 Page 8 of 14 J Mol Model (2021) 27:217
simulations by employing the following equation:
δ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ΔHV
−RT
Vm
sð1Þ
In Eq. (1), ΔH
V
,andV
m
are the heat of vaporization and
molar volume. The MD simulation model that has been used
for calculation of solubility parameter consisted of 32 FPTT
molecules placed in the cubic simulation box. The mentioned
system simulated in the NPT regime for the simulation time of
10 ns employed the OPLS3e force field. In the case of FPTT,
the abovementioned equation yielded the value of the solubil-
ity parameter to be 21.521 MPa
1/2
. To make this value useful,
we have performed the MD simulations in the same setup for
the frequently used excipients, such as polyvinylpyrrolidone
polymer (PVP), maltose, and sorbitol. Solubility parameters
for FPTT and mentioned, frequently used, excipients are sum-
marized in Table 2.
Molecular docking and MD simulations
Receptors of the growth factor increased expression and acti-
vation of receptor tyrosine kinases frequently occur in carci-
nomas of the human breast. Docking was done on Auto Dock-
Vina [76,77] using the proteins 2PSQ, 5AEP, and 2V3Q with
predicted activities (Table S4), platelet-derived growth factor
receptor kinase inhibitor, phobic disorders treatment, and ath-
erosclerosis treatment activities [111]. Different methods
targeting these receptors are in clinical research studies [112,
113]. Several literature surveys show thiourea derivatives as
anticancerous [114,115]. Thus, we choose FPTT as ligand
and selected inhibitors as the target. Figure S4 and Figure S5
demonstrate a docked ligand at the active site of receptors.
The docked ligand forms stable complexes with binding af-
finities of −7.7, −8.4, and −7.0 kcal/mol (Table 3). As a result,
FPTT demonstrates activity against these inhibitors and may
be used as new drugs. The inhibition is a function of binding
modes and affinities of molecules to enzymes [116].
Figure S6 displays the RMSD outcome of the 2PSQ,
5AEP, 2V3Q, and FPTT complex. The 2PSQ, 2V3Q, and
5AEP complexes with FPTT structures were stable after 30,
20, and 30 ns, respectively. Average values and standard de-
viations of 2PSQ, 2V3Q, and 5AEP complexes with FPTT
are, respectively, ~0.211 ± 0.025, ~0.238 ± 0.035, and ~
0.241 ± 0.030 nm of 50-ns simulation. This reflects that
protein-FPTT maintains for the entire simulation time stabili-
ty. MMPBSA values give binding free energy values of
2PSQ, 2V3Q, and 5AEP with FPTT are respectively,
−31.429 ± 3.956, −27.908 ± 3.297, and −26.886 ±
3.500 kcal/mol which means that the inhibitor has better en-
ergy with all the targets (Table 4).
Conclusion
Combinations of DFT and MD simulations were used to iden-
tify the most important reactive sites of FPTT. In this regard,
both MEP and ALIE surfaces revealed that the most important
reactive atom might be sulfur since this atom is characterized
by the lowest MEP and ALIE values. Calculations of the H-
BDE parameter indicate that FPTT should be highly resistant
to the autoxidation mechanism since DFT calculations
showed that all H-BDE values are higher. This also indicates
that FPTT could be stable during the shelf life and that the
formation of genotoxic impurities should not occur. MD
Table 2 Values of
solubility parameters δ
[MPa
1/2
] for FPTT and
selected excipients
Molecules δ[MPa
1/2
]
FPTT 20.521
PVP 18.515
Maltose 28.564
Sorbitol 32.425
Table 3 Docking analysis of receptors with ligands
Receptors
name
Binding
energy
Residues
involved in
hydrogen
bonding
Residues
involved in
electrostatic
interactions
Residues
involved in
hydrophobic
interactions
2PSQ −7.7 ASP644,
LYS517,
VAL495,
ALA515,
LEU633
LYS517,
GLU565,
ASP644
VAL495,
ALA515,
VAL564,
LEU633,
LEU487
5AEP −8.4 ARG980,
LEI392,
ASP994,
LEU983,
ALA880
LEU392,
ASP994,
ASN981
LEU392,
LEU983,
MET929,
LEU885,
ALA880,
VAL863,
TYR931
2V3Q −7.0 PRO260,
LEU261,
LYS63,
ASP271
LYS63,
PRO260,
ASP271,
VAL274,
GLY283,
GLY284
PRO260,
GLY284,
VAL272,
TRP346
Table 4 MMPBSA value of EGFR target of 50-ns simulation
PDB ID Ligand Binding energy
2PSQ FPTT −31.429± 3.956 kcal/mol
2V3Q FPTT −27.908± 3.297 kcal/mol
5AEP FPTT −26.886±3.500 kcal/mol
JMolModel (2021) 27:217 Page 9 of 14 217
simulations identified which atoms have relatively pro-
nounced interactions with water molecules. Analysis of
RDFs MD simulations showed that three atoms (S10, C6,
and C18) are having significant interactions with water.
However, the overall influence of water is low, because in
all cases, the higher g(r) values are at high distances.
Solubility parameters for FPTT and selected excipients have
been calculated also by the application of MD simulations. It
was found that the solubility parameter of FPTT is the closest
to the PVP, meaning that this combination might have the
potential for the development of novel pharmaceutical prod-
ucts. Validation by MD integrated with molecule interactions
shows stability with the target proteins.
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s00894-021-04835-9.
Acknowledgements VC thanks KBITS, Bangalore, and BiSEP
(Department of Biotechnology, Siddaganga Institute of Technology,
Tumakuru), Karnataka.
Code availability The calculations have been carried out using
Gaussian09 and Gaussview version provided by Gaussian Inc.,
Schrodinger Suite 2020-4, GROMACS.
Author contribution All authors contributed to the study conception and
design. Material preparation and data collection and analysis were per-
formed by Y Sheena Mary, Y Shyma Mary, Stevan Armaković, Sanja J
Armaković, Vivek Chandramohan, and Manjunath Dammalli. The ex-
perimental part was done by Anna Bielenica.
Funding The authors, SA and SJA, received the financial support from
the Ministry of Education, Science and Technological Development of
the Republic of Serbia (Grant No. 451-03-68/2020-14/200125).
Declarations
Ethics approval The manuscript is prepared in compliance with the
Ethics in Publishing Policy as described in the Guide for Authors.
Consent to participate The manuscript is approved by all authors for
publication.
Consent for publication The consent for publication was obtained from
all participants.
Conflict of interest The authors declare no competing interests.
References
1. Bielenica A, Stefańska J, StępieńK, Napiórkowska A,
Augustynowicz-KopećE, Sanna G, Madeddu S, Boi S, Giliberti
G, Wrzosek M, Struga M (2015) Synthesis, cytotoxicity and
antimicrobial activity of thiourea derivatives incorporating 3-
(trifluoromethyl)phenyl moiety. Eur. J. Med. Chem. 101:111–
125. https://doi.org/10.1016/j.ejmech.2015.06.027
2. Bielenica A, StępieńK, Napiórkowska A, Augustynowicz-Kopeć
E, Krukowski S, Włodarczyk M, Struga M (2016) Synthesis and
antimicrobial activity of 4-chloro-3-nitrophenylthiourea deriva-
tives targeting bacterial type II topoisomerases. Chem. Biol.
Drug Des. 87:905–917. https://doi.org/10.1111/cbdd.12723
3. Sriram D, Yogeeswari P, Dinakaran M, Thirumurugan R (2007)
Antimycobacterial activity of novel 1-(5-cyclobutyl-1,3-oxazol-2-
yl)-3-(sub)phenyl/pyridylthiourea compounds endowed with high
activity toward multidrug resistant mycobacterium tuberculosis. J.
Antimicrob. Chemother. 59:1194–1196. https://doi.org/10.1093/
jac/dkm085
4. Bhowruth V, Brown AK, Reynolds RC, Coxon GD, Mackay SP,
Minnikin DE, Besra GS (2006) Symmetrical and unsymmetrical
analogues of isoxyl active agents against mycobacterium tubercu-
losis. Bioorg. Med. Chem. Lett. 16:4743–4747. https://doi.org/10.
1016/j.bmcl.2006.06.095
5. Mishra A, Batra S (2013) Thiourea and guanidine derivatives as
antimalarial and antimicrobial agents. Curr. Top. Med. Chem. 13:
2011–2025. https://doi.org/10.2174/1568026611319990126
6. Vega-Pérez JM, Periñán I, Argandoña M, Vega-Holm M, Palo-
Nieto C, Burgos-Morón E, López-Lázaro M, Vargas C, Nieto JJ,
Iglesias-Guerra F (2012) Isoprenyl thiourea and urea derivatives
as new farnesyl diphosphate analogues, synthesis and in vitro an-
timicrobial and cytotoxic activities. Eur. J. Med. Chem. 58:591–
612. https://doi.org/10.1016/j.ejmech.2012.10.042
7. Kumbhare RM, Dadmal T, Kosurkar U, Sridhar V, Rao JV (2012)
Synthesis and cytotoxic evaluation of thiourea and N-bis-
benzothiazole derivatives: a novel class of cytotoxic agents.
Bioorg. Med. Chem. Lett. 22:453–455. https://doi.org/10.1016/j.
bmcl.2011.10.106
8. Bielenica A, Kędzierska E, Koliński M, Kmiecik S, Koliński A,
Fiorino F, Severino B, Magli E, Corvino A, Rossi I, Massarelli P,
KoziołAE, Sawczenko A, Struga M (2016) 5-HT2 receptor affin-
ity, docking studies and pharmacological evaluation of a series of
1,3-disubstituted thiourea derivatives. Eur. J. Med. Chem. 116:
173–186. https://doi.org/10.1016/j.ejmech.2016.03.073
9. Bielenica A, Kedzierska E, Fidecka S, Maluszynska H, Miroslaw
B, Koziol AE, Stefanska J, Madeddu S, Giliberti G, Sanna G,
Struga M (2015) Synthesis, antimicrobial and pharmacological
evaluation of thiourea-derivatives of 4H-1,2,4-triazole. Lett Drug
Des Discov 12:263–276. https://doi.org/10.2174/
1570180811666141001010044
10. Struga M, Kossakowski J, Koziol AE, Lis T, Kedzierska E,
Fidecka S (2009) Synthesis and pharmacological activity of thio-
urea derivatives of 1,7,8,9-tetramethyl-4-azatricyclo[5.2.1.02,
]dec-8-ene-3,5-dione. Lett Drug Des Discov 6:445–450. https://
doi.org/10.2174/157018009789057517
11. Stefanska J, Szulczyk D, Koziol AE, Miroslaw B, Kedzierska E,
Fidecka S, Busonera B, Sanna G, Giliberti G, La Colla P, Struga
M (2012) Disubstituted thiourea derivatives and their activity on
CNS, synthesis and biological evaluation. Eur. J. Med. Chem. 55:
205–213. https://doi.org/10.1016/j.ejmech.2012.07.020
12. Struga M, Kossakowski J, Kedzierska E, Fidecka S, Stefańska J
(2007) Synthesis and pharmacological activity of urea and thio-
urea derivatives of 4-azatricyclo[5.2.2.0, 2,6]undec-8-ene-3,5-
dione. Chem Pharm Bull (Tokyo) 55:796–799. https://doi.org/
10.1248/cpb.55.796
13. Suresh GP, Suhas R, Kapfo W, Gowda DC (2011) Urea/thiourea
derivatives of quinazolinone-lysine conjugates: synthesis and
structure activity relationships of a new series of antimicrobials.
Eur. J. Med. Chem. 46:2530–2540. https://doi.org/10.1016/j.
ejmech.2011.03.041
217 Page 10 of 14 J Mol Model (2021) 27:217
14. Chikhalia KH, Patel MJ (2009) Design, synthesis and evaluation
of some 1,3,5-triazinyl urea and thiourea derivatives as antimicro-
bial agents. J Enzym Inhib Med Chem 24:960–966. https://doi.
org/10.1080/14756360802560966
15. Li WQ, Wang XL, Qian K, Liu YQ, Wang CY, Yang L, Tian J,
Morris-Natschke SL, Zhou XW, Lee KH (2013) Design, synthesis
and potent cytotoxic activity of novel popophylotoxin derivatives.
Bioorg. Med. Chem. 21:2363–2369. https://doi.org/10.1016/j.
bmc.2013.01.069
16. Koca I, Ozgür A, Cos KA, Tutar Y (2013) Synthesis and antican-
cer activity of acyl thioureas bearing pyrazole moiety. Bioorg.
Med. Chem. 21:3859–3865. https://doi.org/10.1016/j.bmc.2013.
04.021
17. KarakuşS, GünizKüçükgüzel S, Küçükgüzel I, De Clercq E,
Pannecouque C, Andrei G, Snoeck R, Sahin F, Bayrak OF
(2009) Synthesis, antiviral and anticancer activity of some novel
thioureas derived from N-(4-nitro-2-phenoxyphenyl)-
methanesulfonamide. Eur. J. Med. Chem. 44:3591–3595. https://
doi.org/10.1016/j.ejmech.2009.02.030
18. Di Grandi MJ, Curan KJ, Feigelson G, Prashad A, Ross AA,
Visalli R, Fairhurst J, Feld B, Bloom JD (2004) Thiourea inhibi-
tors of herpesviruses, part 3. Inhibitors of varicella zoster virus.
Bioorg. Med. Chem. Lett. 14:4157–4160. https://doi.org/10.1016/
j.bmcl.2004.06.025
19. Bloom JD, DiGrandi MJ, Dushin RG, Curran KJ, Ross AA,
Norton EB, Terefenko E, Jones TR, Feld B, Lang SA (2003)
Thiourea inhibitors of herpes viruses, part 1, bis-(aryl)thiourea
inhibitors of CMV. Bioorg. Med. Chem. Lett. 13:2929–2932.
https://doi.org/10.1016/S0960-894X(03)00586-9
20. Khan MT, Ather A, Thompson KD, Gambari R (2005) Extracts
and molecules from medicinal plants against herpes simplex vi-
ruses. Antivir. Res. 67:107–119. https://doi.org/10.1016/j.
antiviral.2005.05.002
21. Ren J, Diprose J, Warren J, Esnouf RM, Bird LE, Ikemizu S,
Slater M, Milton J, Balzarini J, Stuart DI, Stammers DK (2000)
Phenylethylthiazolylthiouread (PETT) non-nucleoside inhibitors
of HIV-1 and HIV-2 reverse transcriptases. J. Biol. Chem. 275:
5633–5639. https://doi.org/10.1074/jbc.275.8.5633
22. Abu-Melha S (2013) Synthesis and antimicrobial activity of some
new heterocycles incorporating the pyrazolopyridine moiety.Arch
Pharm Weinheim 346:912–921. https://doi.org/10.1002/ardp.
201300195
23. Yang W, Liu H, Li M, Wang F, Zhou W, Fan J (2012) Synthesis,
structures and antibacterial activities of benzyolthiourea deriva-
tives and their complexes with cobalt. J. Inorg. Biochem. 116:
97–105. https://doi.org/10.1016/j.jinorgbio.2012.08.001
24. Plutín AM, Mocelo R, Alvarez A, Ramos R, Castellano EE,
Cominetti MR, Graminha AE, Ferreira AG, Batista AA (2014)
On the cytotoxic activity of Pd(II) complexes of N,N-disubstitut-
ed-N’-acyl thioureas. J. Inorg. Biochem. 134:76–82. https://doi.
org/10.1016/j.jinorgbio.2014.01.022
25. Arslan H, Duran N, Borekci G, Koray Ozer C, Akbay C (2009)
Antimicrobial activity of some thiourea derivatives and their nick-
el and copper complexes. Molecules 14:519–527. https://doi.org/
10.3390/molecules14010519
26. Batey RA, Powell DA (2000) A general synthetic method for the
formation of substituted 5-aminotetrazoles from thioureas, a strat-
egy of diversity amplification. Org. Lett. 2:3237–3240. https://doi.
org/10.1021/ol006465b
27. Min LJ, Zhai ZW, Shi YX, Han L, Tan CX, Weng JQ, Li BJ,
Zhang YG, Liu XH (2020) Synthesis and biological activity of
acyl thiourea containing difluoromethyl pyrazole motif.
Phosphorus Sulfur Silicon Relat. Elem. 195:22–28. https://doi.
org/10.1080/10426507.2019.1633530
28. Eshkil F, Eshghi H, Saljooghi AS, Bakavoli M, Rahimizadeh M
(2017) Benzothiazole thiourea derivatives as anticancer agents:
design, synthesis and biological screening. Russian J Bioorg
Chem 43:576–582. https://doi.org/10.1134/
S10681620017050065
29. Moeker J, Teruya K, Rossit S, Wilkinson BL, Lopez M, Bornaghi
LF, Innocenti A, Supuran CT, Poulsen SA (2012) Design and
synthesis of thiourea compounds that inhibit transmembrane an-
chored carbonic anhydrases. Bioorg. Med. Chem. 20:2392–2404.
https://doi.org/10.1016/j.bmc.2012.01.052
30. Sun Y, Shan Y, Li C, Si R, Pan X, Wang B, Zhang J (2017)
Discovery of novel anti-angiogenesis agents. Part 8: diaryl thio-
urea bearing 1H-indazole-3-amine as multi-target RTKs inhibi-
tors. Eur. J. Med. Chem. 141:373–385. https://doi.org/10.1016/j.
ejmech.2017.10.008
31. Alimohammadi A, Mostafavi H, Mahdavi M (2020) Thiourea
derivatives based on the dapsone-naphthoquinone hybrid as anti-
cancer and antimicrobial agents: in vitro screening and molecular
docking studies. Chemistry Select 5:847–852. https://doi.org/10.
1002/slct.201903179
32. Saeed A, Qamar R, Fattah TA, Florke U, Erben MF (2017) Recent
developments in chemistry, coordination, structure and biological
aspects of 1-(acyl/aroyl)-3-(substituted)thioureas. Res. Chem.
Intermed. 43:3053–3093. https://doi.org/10.1007/s11164-016-
2811-5
33. Markov SV, Horvath AK, Silaghi-Dumitrescu R, Gao Q (2014)
Recent developments in chemistry of thiourea oxides. Chemistry
20:14164–14176. https://doi.org/10.1002/chem.201403453
34. Tian Z, Lai F, Heil T, Cao S, Antonietti M (2020) Synthesis of
carbon frameworks with N, O and S-linked pores from gallic acid
and thioureafor superior CO2 adsorption and supercapacitors. Sci
China Mater 63:748–710. https://doi.org/10.1007/s40843-019-
1254-9
35. Shakeel A, Altaf AA, Qureshi AM, Badshah A (2016) Thiourea
derivatives in drug design and medicinal chemistry: a short re-
view. J Drug Des Med Chem 2:10–20. https://doi.org/10.11648/
j.jddmc.20160201.12
36. Saeed A, Mustafa MN, Zain-Ul-Abideen M, Shabir G, Erben MF,
Florke U (2019) Current developments in chemistry, coordination,
structure and biological aspects of 1-(acyl/aroyl)-3-(substituted)
thioureas: advances continue. Sulfur Chem 40:312–350. https://
doi.org/10.1080/17415993.2018.1551488
37. Khan E, Khan S, Gul Z, Muhammad M (2020) Medicinal impor-
tance, coordination chemistry with selected metals (Cu, Ag, Au)
and chemosensing of thiourea derivatives, A review. Critical
Reviews in Analytical Chemistry. https://doi.org/10.1080/
10408347.2020.1777523
38. Bai W, Ji J, Huang Q, Wei W (2020) Synthesis and evaluation of
new thiourea derivatives as antitumor and antiangiogenic agents.
Tetrahedron Lett. 61:152366. https://doi.org/10.1016/j.tetlet.
2020.152366
39. Menon VV, Mary YS, Mary YS, Panicker CY, Bielenica A,
Armakovic S, Armakovic SJ, Van Alsenoy C (2018) Combined
spectroscopic, DFT, TD-DFT and MD study of newly synthesized
thiourea derivative. J. Mol. Struct. 1155:184–195. https://doi.org/
10.1016/j.molstruc.2017.10.093
40. Aswathy VV, Mary YS, Jojo PJ, Panicker CY, Bielenica A,
Armakovic S, Armakovic SJ, Brozka P, Krukowski S, Van
Alsenoy C (2017) Investigation of spectroscopic, reactive, trans-
port and docking properties of 1-(3,4-dichlorophenyl)-3-[3-
(trifluoromethyl)phenyl]thiourea (ANF:6): combined experimen-
tal and computationalstudy. J. Mol. Struct. 1134:668–680. https://
doi.org/10.1016/j.molstruc.2017.01.016
41. War JA, Jalaja K, Mary YS, Panicker CY, Armakovic S,
Armakovic SJ, Srivastava SK, Van Alsenoy C (2017)
Spectroscopic characterization of 1-[3-(1H-imidaozl-1-
yl)propyl]-3-phenylthiourea and assessment of reactive and opto-
electronic properties employing DFT calculations and molecular
JMolModel (2021) 27:217 Page 11 of 14 217
dynamics simulations. J. Mol. Struct. 1129:72–85. https://doi.org/
10.1016/j.molstruc.2016.09.063
42. Mary YS, Aswathy VV, Panicker CY, Bielenica A, Brzozka P,
Savczenko O, Armakovic S, Armakovic SJ, Van Alsenoy C
(2016) Spectroscopic, single crystal XRD structure, DFT and mo-
lecular dynamics investigation of 1-(3-chloro-4-fluorophenyl)-3-
[3-(trifluoromethyl)phenyl]thiourea. RSC Adv. 6:111997–
112015. https://doi.org/10.1039/C6RA21396K
43. Armakovic S, Armakovic SJ, Koziel S (2017) Optoelectronic
properties of curved carbon systems. Carbon 111:371–379.
https://doi.org/10.1016/j.carbon.2016.10.022
44. Murthy PK, Suneetha V, Smitha M, Mary YS, Armakovic S,
Armakovic SJ, Rao RS, Suchetan PA, Al-Saadi AA, Pavithran
R (2019) Synthesis, conformational, characterization and reactiv-
ity study of 1,7-bis(4-bromophenyl)heptanes-1,7-dione. J. Mol.
Struct. 1175:269–279. https://doi.org/10.1016/j.molstruc.2018.
08.003
45. Prasad KS, Pillai RR, Armakovic S, Armakovic SJ (2019)
Photophysical properties and theoretical investigations of newly
synthesized pyrene-naphthalene based Sciff base ligand and its
copper(II) complexes. Inorganica Chim Acta 486:698–703.
https://doi.org/10.1016/j.ica.2018.11.045
46. Tomic BT, Abraham CS, Pelemis S, Armakovic SJ, Armakovic S
(2019) Fullerene C24 as a potential carrier of ephedrine drug-a
computational study of interactions and influence of temperature.
Phys. Chem. Chem. Phys. 21:23329–23337. https://doi.org/10.
1039/c9cp04534a
47. Becke AD (1993) Density functional thermochemistry. III. The
role of exact exchange. J Chem Phys 98:5648–5652. https://doi.
org/10.1063/1.464913
48. Becke AD (1988) Density functional exchange energy approxi-
mation with correct asymptotic behaviour. Phys. Rev. A 38:3098–
3100. https://doi.org/10.1103/PhysRevA.38.3098
49. Foresman JB, Frisch E (1996)Exploring chemistrywith electronic
structure methods: a guide to using Gaussian, Pittsburg, PA
50. Dennington R, Keith T, Millam J (2009) Gaussview, Version 5.
Semichem Inc., ShawneeMission, KS
51. Gaussian 09, Revision B.01, Frisch MJ, Trucks GW, Schlegel
HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G,
Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M,
Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G,
Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R,
Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai
H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F,
Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN,
Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A,
Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM,
Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J,
Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R,
Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski
VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels
AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ
(2010) Gaussian, Inc., Wallingford CT
52. Martin JML, Van Alsenoy C (2007) GAR2PED, a program to
obtain a potential energy distribution from a Gaussian archive
record. University of Antwerp, Belgium
53. Bochevarov AD, Harder E, Hughes TF, Greenwood JR, Braden
DA, Philipp DM, Rinaldo D, Halls MD, Zhang J, Friesner RA
(2013) Jaguar: a high performance quantum chemistry software
program with strengths in life and materials sciences. Int. J.
Quantum Chem. 113:2110–2142. https://doi.org/10.1002/qua.
24481
54. Jacobson LD, Bochevarov AD, Watson MA, Hughes TF, Rinaldo
D, Ehrlich S, Steinbrecher TB, Vaitheeswaran S, Philipp DM,
Halls MD (2017) Automated transition state search and its
application to diverse types of organic reactions. J. Chem.
Theory Comput. 13:5780–5797. https://doi.org/10.1021/acs.jctc.
7b00764
55. Schrodinger Release 2020–3: Jaguar, Schrodinger, LLC, New
York, NY, 2020 (n.d.)
56. Bowers KJ, Chow DE, Xu H, Dror RO, Eastwood MP,
Gregeersen BA, Klepeis JL, Kolossvary I, Moraes MA,
Sacerdoti FD (2006) Scalable algorithms for molecular dynamics
simulations on commodity clusters, in: SC’06 Proc. 2006 ACM/
IEEE Conf. Supercomput. IEEE, p.43
57. Schrodinger Release 2020-3: Desmond molecular dynamics sys-
tem, DE.Shaw Research, New York, NY, 2020. Maestro-
Desmond interoperability tools, Schrodinger, New York, NY,
2020. (n.d.)
58. Schrodinger Release 2020-3: Maestro, Schrodinger, LLC, New
York, NY, 2020 (n.d.)
59. Lee C, Yang W, Parr RG (1988) Development of the Colle-
Salvetti correlation-energy formula into a functional of the elec-
tron density. Phys. Rev. B 37:785–789. https://doi.org/10.1103/
PhysRevB.37.785
60. Vosko SH, Wilk L, Nusair M (1980) Accurate spin-dependent
electron liquid correlation energies for local spin density calcula-
tions: a critical analysis. Can. J. Phys. 58:1200–1211. https://doi.
org/10.1139/p80-159
61. Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) Ab
initio calculation of vibrational absorption and circular dichroism
spectra using density functional force fields. J. Phys. Chem. 98:
11623–11627. https://doi.org/10.1021/j100096a001
62. Harder E, Damm W, Maple J, Wu C, Reboul M,Xiang JY, Wang
L, Lupyan D, Dahlgren MK, Knight JL, Kaus JW, Cerutti DS,
Krilov G, Jorgensen WL, Abel R, Friesner RA (2016) OPLS3: a
force field providing broad coverage of drug-like small molecules
and proteins. J. Chem. Theory Comput. 12:281–296. https://doi.
org/10.1021/acs.jctc.5b00864
63. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman
W (2010) Prediction of absolute salvation free energies using mo-
lecular dynamics free energy perturbation and the OPLS force
field. J. Chem. Theory Comput. 6:1509–1519. https://doi.org/10.
1021/ct900587b
64. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development
and testing of the OPLS all-atom force field conformational ener-
getic and properties of organic liquids. J. Am. Chem. Soc. 118:
11225–11236. https://doi.org/10.1021/ja9621760
65. Jorgensen WL, Tirado-Rives J (1988) The OPLS [optimized po-
tentials for liquid simulations] potential for proteins, energy min-
imizations for crystals of cyclic peptides and crambin. J. Am.
Chem. Soc. 119:1657–1666. https://doi.org/10.1021/ja00214a001
66. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J
(1981) Interaction models for water in relation to protein hydra-
tion, in: Intermolecular Forces, Springer pp. 331–342
67. Oostenbrink C, Villa A, Mark AE, Van Gunsteren WF (2004) A
biomolecular force field based on the free enthalpy of hydration
and solvation: the GROMOS force field parameter sets 53A5 and
53A6. J. Comput. Chem. 25(13):1656–1676. https://doi.org/10.
1002/jcc.20090
68. Hess B, Kurzner C, van der Spoel D, Lindahl E (2008)
GROMACS 4: algorithms for highly efficient, load balanced
and scalable molecular simulation. J. Chem. Theory Comput.
4(3):435–447. https://doi.org/10.1021/ct700301q
69. Webb B, Saji A (2016) Comparative protein structure modelling
using Modeller. Curr. Protoc. Bioinformatics 54:5.6.1–5.6.37.
https://doi.org/10.1002/cpbi.3
70. Berendsen HJC, van der Spoel D, van Drunen R (1995)
GROMACS: a message passing parallel molecular dynamics im-
plementation. Comput. Phys. Commun. 91(1–3):43–56. https://
doi.org/10.1016/0010-4655(95)00042-E
217 Page 12 of 14 J Mol Model (2021) 27:217
71. Lindahl E, Hess B, van der Spoel D (2001) GROMACS3.0: a
package for molecular simulation and trajectory analysis.
Molecular Modeling Annual 7:306–317. https://doi.org/10.1007/
s008940100045
72. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molec-
ular dynamics. J. Mol. Graph. 14(1):33–38. https://doi.org/10.
1016/0263-7855(96)00018-5
73. Schrodinger L (2010) The PyMOL molecular graphics system,
version 1.3r1
74. Turner P (2005) XMGRACE, version 5.1.19, Center for Coastal
and land-margin research. Oregon Graduate Institute of Science
and Technology, Beaverton
75. Miller III BR, McGee Jr TD, Swails JM, Homeyer N, Gohlke H,
Roitberg AE (2012) MMPBSA, py: an efficient program for end-
state free energy calculations. J. Chem. Theory Comput. 8(9):
3314–3321. https://doi.org/10.1021/ct300418h
76. Trott O, Olson AJ (2010) AutoDockVina: improving the speed
and accuracy of docking with a new scoring function, efficient
optimization and multithreading. J. Comput. Chem. 31:455–461.
https://doi.org/10.1002/jcc.21334
77. Haress NG, Al-Omary F, El-Emam AA, Mary YS, Panicker CY,
Al-Saadi AA, War JA, Van Alsenoy C (2015) Spectroscopic in-
vestigation (FT-IR and FT-Raman), vibrational assignments,
HOMO-LUMO analysis and molecular docking study of 2-
(adamantan—1yl)-5-(4-nitrophenyl)-1,3,4-oxadiazole.
Spectrochim. Acta 135:973–983. https://doi.org/10.1016/j.saa.
2014.07.077
78. Das KGV, Panicker CY, Narayana B, Nayak PS, Sarojini BK, Al-
Saadi AA (2015) FT-IR, molecular structure, first order
hyperpolarizability, NBO analysis, HOMO and LUMO and
MEP analysis of 1-(10H-phenothiazin-2-yl)ethanone by HF and
densityfunctional methods. Spectrochim. Acta 135:162–171.
https://doi.org/10.1016/j.saa.2014.06.155
79. Panicker CY, Varghese HT, George A, Thomas PKV (2010) FT-
IR, FT-Raman and ab initio studies of 1,3-diphenyl thiourea. Eur.
J. Chem. 1:173–178. https://doi.org/10.5155/eurjchem.1.3.173-
178.42
80. Mary YS, Panicker CY, Narayana B, Samshuddin S, Sarojini BK,
Van Alsenoy C (2014) FT-IR, molecular structure, HOMO-
LUMO, MEP, NBO analysis and first order hyperpolarizabilityof
methyl 4,4″-difluoro-5-methoxy-1,1′,3′1″-tertphenyl-4′-carboxyl-
ate. Spectrochim. Acta 133:480–488. https://doi.org/10.1016/j.
saa.2014.06.031
81. Mary YS, Panicker CY, Yamuna TS, SiddegowdaMS, Yathirajan
HS, Al-Saadi AA, Van Alsenoy C (2014) Theoretical investiga-
tions on the molecular structure, vibrational spectra, HOMO-
LUMO and NBO analysis of 9-[3-(dimethylamino) propyl]-2-
trifluoro-methyl-9H-thioxanthen-9-ol. Spectrochim. Acta 132:
491–501. https://doi.org/10.1016/j.saa.2014.05.016
82. Yang W, Zhou W, Zhang Z (2007) Structural and spectroscopic
study of N-2-fluorobenozyl-N-4-methoxyphenylthiourea. J. Mol.
Struct. 828:46–53. https://doi.org/10.1016/j.molstruc.2006.05.
033
83. Colthup NB, Daly LH, Wiberly SE (1975) Introduction of infrared
and Raman Spectroscopy. Academic Press, New York
84. Mary YS, Varghese HT, Panicker CY, Ertan T, Yildiz I, Temiz-
Arpaci O (2008) Vibrational spectroscopic studies and ab initio
calculations of 5-nitro-2-(p-fluorophenyl)benzoxazole.
Spectrochim. Acta 71:566–571. https://doi.org/10.1016/j.saa.
2007.12.041
85. Mary YS, Panicker CY, Sapnakumari M, Narayana B, Sarojini
BK, Al-Saadi AA, Van Alsenoy C, War JA (2015) Molecular
structure, FT-IR, vibration assignments, HOMO-LUMO, MEP,
NBO analysis and molecular docking study of ethyl-6-(4-
chlorophenyl)-4-(4-fluorophenyl)-2-oxocyclohex-3-ene-1-
carboxylate. Spectrochim Acta 138:73–84. https://doi.org/10.
1016/j.saa.2014.11.012
86. Roeges NPG (1994) A guide to the complete interpretation of
infrared spectra of organic structures. John Wiley and Sons Inc.,
New York
87. Socrates G (1981) Infrared characteristic group frequencies. John
Wiley and Sons, New York
88. Nigam S, Patel MM, Ray A (2000) Normal coordinate analysis
and CNDO/II calculations of isonitrosopropiohenone
(propiophenone oxime) and its semicarbazone and
thiosemicarbazone derivatives, synthesis and characterization of
their metal complexes. J. Phys. Chem. Solids 61:1389–1398.
https://doi.org/10.1016/S0022-3697(00)0025-1
89. Varsanyi G (1974) Assignments of vibrational spectra of seven
hundred benzene derivatives. Wiley, New York
90. Raju R, Panicker CY, Nayak PS, Narayana B, Sarojini BK, Van
Alsenoy C, Al-Saadi AA (2015) FT-IR, molecular structure, first
order hyperpolarizability, MEP, HOMO and LUMO analysis and
NBO analysis of 4-[(3-acetylphenyl)amino]-2-methylidene-4-
oxobutanoic acid. Spectrochim. Acta 134:63–72. https://doi.org/
10.1016/j.saa.2014.06.051
91. Sebastian SHR, Al-Alshaikh MA, El-Emam AA, Panicker CY,
Zitko J, Dolezal M, Van Alsenoy C (2016) Spectroscopic, quan-
tum chemical studies, Fukui functions, in vitro antiviral activity
and molecular docking of 5-chloro-N-(3-nitrophenyl)pyrazine-2-
carboxamide. J. Mol. Struct. 1119:188–199. https://doi.org/10.
1016/j.molstruc.2016.04.088
92. El-Azab AS, Jalaja K, Abdel-Aziz AAM, Al-Obaid AM, Mary
YS, Panicker CY, Van Alsenoy C (2016) Spectroscopic analysis
(FT-IR, FT-Raman and NMR) and molecular docking study of
ethyl 2-(4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-ylthio)-ace-
tate. J. Mol. Struct. 1119:451–461. https://doi.org/10.1016/j.
molstruc.2016.05.004
93. NBO Version 3.1, E. D. Glendening, A. E. Reed, J. E. Carpenter,
and F. Weinhold, Pittsburgh, A, Gaussian Inc. 2003
94. Mary YS, Panicker CY, Sapnakumari M, Narayana B, Sarojini
BK, Al-Saadi AA, Van Alsenoy C, War JA, Fun HK (2015)
Infrared spectrum, structural and optical properties and molecular
docking study of 3-(4-fluorophenyl)-5-phenyl-4,5-dihdyro-1H-
pyrazole-1-carbaldehyde. Spectrochim. Acta 138:529–538.
https://doi.org/10.1016/j.saa.2014.11.041
95. Sheeja SR, Mangalam NA, Kurup MRP, Mary YS, Raju K,
Varghese HT, Panicker CY (2010) Vibrational spectroscopic
studies and computational study of quinoline-2-carbaldehyde ben-
zoyl hydrazone. J. Mol. Struct. 973:36–46. https://doi.org/10.
1016/j.molstruc.2010.03.016
96. Mary YS, Panicker CY, Sapnakumari M, Narayana B, Sarojini
BK, Al-Saadi AA, Van Alsenoy C, War JA, Fun HK (2015)
Molecular structure, FT-IR, vibrational assignments, HOMO-
LUMO analysis and molecular docking study of 1-[5-(4-
Bromophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-
yl]ethanone. Spectrochim. Acta 136:473–482. https://doi.org/10.
1016/j.saa.2014.09.060
97. Mary YS, Miniyar PB, Mary YS, Resmi KS, Panicker CY,
Armakovic S, Armakovic SJ, Thomas R, Sureshkumar B (2018)
Synthesis and spectroscopic study of three new oxadiazole deriv-
atives with detailed computational evaluation of their reactivity
and pharmaceutical potential. J. Mol. Struct. 1173:469–480.
https://doi.org/10.1016/j.molstruc.2018.07.076
98. Mary YS, Mary YS, Thomas R, Narayana B, Samshuddin S,
Sarojini BK, Armakovic S, Armakovic SJ, Pillai GG (2019)
Theoretical studies on the structure and various physic-chemical
and biological properties of a terphenyl derivative with immense
anti-protozoan activity. Polycycl. Aromat. Compd. https://doi.org/
10.1080/10406638.2019.1624974
JMolModel (2021) 27:217 Page 13 of 14 217
99. Shafieyoon P, Mehdipour E, Mary YS (2019) Synthesis, charac-
terization and biological investigation of glycine based sulfon-
amide derivative and its complex: vibration assignment, HOMO-
LUMO analysis, MEP and molecular docking. J. Mol. Struct.
1181:244–252. https://doi.org/10.1016/j.molstruc.2018.12.067
100. Politzer P, Murray JS (2002) The fundamental nature and role of
the electrostatic potential in atoms and molecules. Theor. Chem.
Accounts 108:134–142. https://doi.org/10.1007/s00214-002-
0363-9
101. Politzer P, Laurence PR, Jayasuriya K (1985) Molecular electro-
static potentials: an effective tool for the elucidation of biochem-
ical phenomena. Environ. Health Perspect 61:191–202. https://
doi.org/10.1289/ehp.8561191
102. Politzer P, Murray JS, Bulat FA (2010) Average local ionization
energy: a review. J. Mol. Model. 16:1731–1742. https://doi.org/
10.1007/s00894-010-0709-5
103. Politzer P, Abu-Awwad F, Murray JS (1998) Comparison of den-
sity functional and Hartree-Fock average local ionization energies
on molecular surfaces. Int J. Quantum Chem 69:607–613. https://
doi.org/10.1002/(SICI)1097-461X(1998)69:4<607::AID-
QUA18>3.0.CO;2-W
104. Andersson T, Broo A, Evertsson E (2014) Prediction of drug
candidate’s sensitivity toward autoxidation: computational esti-
mation of CH dissociation energies of carbon-centered radicals.
J. Pharm. Sci. 103:1949–1955. https://doi.org/10.1002/jps.23986
105. Raillard SP, Bercu J, Baertschi SW, Riley CM (2010) Prediction
of drug degradation pathways leading to structural alerts for po-
tential genotoxic impurities. Org Process Rev Dev 14:1015–1020.
https://doi.org/10.1021/op100007q
106. Wright JS, Shadnia H, Chepelev LL (2009) Stability of carbon-
centered radicals: effect of functional groups on the energetics of
addition of molecular oxygen. J. Comput. Chem. 30:1016–1026.
https://doi.org/10.1002/jcc.21124
107. Gryn’ova G, Hodgson JL, Coote ML (2011) Revising the mech-
anism of polymer autoxidation. Org Biomol Chem 9:480–490.
https://doi.org/10.1039/C0OB00596G
108. Greenhalgh DJ, Williams AC, Timmins P, York P (1999)
Solubility parameters as predictors of miscibility in solid
dispersions. J. Pharm. Sci. 88:1182–1190. https://doi.org/10.
1021/js9900856
109. Rowe RC (1988) Adhesion of film coatings to tablet surfaces- a
theoretical approach based on solubility parameters. Int. J. Pharm.
41:219–222. https://doi.org/10.1016/0378-5173(88)90195-0
110. Rowe RC (1989) Interactions in coloured powders and tablet for-
mulations: a theoretical approach based on solubility parameters.
Int. J. Pharm. 53:47–51. https://doi.org/10.1016/0378-5173(89)
90360-8
111. Lagunin A, Stepanchikova A, Filimonov D, Poroikov V (2000)
PASS: prediction of activity spectra for biologically active sub-
stances. Bioinformatics 16:747–748. https://doi.org/10.1093/
bioinformatics/16.8.747
112. Nahata R, Hortobagyi GN, Esteva FJ (2003) Growth factor recep-
tors in breast cancer: potential for therapeutic intervention.
Oncologist 8:5–17. https://doi.org/10.1634/theoncologist.8-15
113. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M,
Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon
DS (2006) Epidermal growth factor receptor (EGFR) signalling
in cancer. Gene 17:2–16. https://doi.org/10.1016/j.gene.2005.10.
018
114. Alqasoumi SI, Alsaid MS, Abdel-Kader MS, Ghorab MM (2015)
Semisynthsis of novel sulphonamides, thioureas and
biphenylsulfones as a new class of anticancer agents by using L-
Norephedrine as strategic starting material. Acta Poloniae
Pharmaceutica-Drug Research 72:1183–1191
115. Kumar V, Kumar A, Sureshbabu VV, Chimni SS (2014)
Synthesis and stereochemistry-activity relationship of chiral thio-
urea derivatives as potential anticancer agents. Anti Cancer
Agents Med. Chem. 14:910–920. https://doi.org/10.2174/
18715206113136660368
116. Yang HY, Ahmad ZA, Song Y (2020) Molecular insights for the
role of key residues of calreticulin in its binding activities.
Comput. Biol. Chem. 85:107228. https://doi.org/10.1016/j.
compbiolchem.2020.107228
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tional claims in published maps and institutional affiliations.
217 Page 14 of 14 J Mol Model (2021) 27:217
