Synthesis, crystal structure, in-silico ADMET, molecular docking and dynamics simulation studies of thiophene-chalcone analogues

Article abstract of DOI:10.1016/j.molstruc.2021.131365

A novel thiophene-based chalcone derivatives, 3-(pyridin-4-yl)-1-(thiophen-2-yl)prop-2-en-1-one (Compound 1) and 3-mesityl-1-(thiophen-2-yl)prop-2-en-1-one (Compound 2) were synthesized and single crystals were grown using slow evaporation technique. The structure of the synthesized compound was confirmed using mass spectroscopy, ¹H-NMR and FTIR spectroscopy. Single crystal X-ray structural analysis reveals that both crystals are crystallized under a monoclinic P21/n space group. C-H…O, C-H…Pi and Pi…Pi intra and intermolecular hydrogen bond interactions of compound 1 and C18-H18C…O7 (2.638 ?) and C3-H3…S1 (2.915 ?) intermolecular interactions in compound 2 contributed to molecular stability. The thiophene-chalcones analogues were screened for the in-sillico studies to understand the antibacterial activity. Molecular docking study was analyzed for the compound 1 and 2 with Penicillin binding proteins (PDB:1MWT) and Staphylocoagulase (PDB:1NU7) of MRSA. Compound 1 showed -6.0 kcal/mol for both Penicillin binding proteins and Staphylocoagulase while compound 2 showed the binding score -6.9 kcal/mol for 1MWT and -7.1 kcal/mol for 1NU7 protein, respectively. The crystallized compounds were also examined for their ADMET analysis and it was observed that there was no AMES toxicity in both compounds. Compound 1 and 2 were also showed 0.529 log mg/kg/day and 1.096 log mg/kg/day maximum tolerated dose (human), respectively. Ultimately, molecular dynamics simulation of compound 1 and 2 confirmed the best possible interaction and stability in the active site of INU7 and allosteric site of IMWT proteins for 20 ns.

Full text of DOI:10.1016/j.molstruc.2021.131365

Journal of Molecular Structure 1247 (2022) 131365
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, crystal structure, in-silico ADMET, molecular docking and
dynamics simulation studies of thiophene-chalcone analogues
S. Nanjundaswamya, Gurumallappaa, M.K. Hemab, C.S. Karthika,∗
,
Jothi Ramalingam Rajabatharc, Selvaraj Arokiyarajd, N.K. Lokanathb, P. Mallua,∗
a Department of Chemistry, SJCE, JSS Science and Technology University, Mysuru, Karnataka 570 006, India
b Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru, Karnataka 570 006, India
c Department of Chemistry, King Saud University, P.O. Box.2455, Riyad 11451, Saudi Arabia
d Department of Food Science and Biotechnology, Sejong University, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel thiophene-based chalcone derivatives, 3-(pyridin-4-yl)-1-(thiophen-2-yl)prop-2-en-1-one (Com-
pound 1) and 3-mesityl-1-(thiophen-2-yl)prop-2-en-1-one (Compound 2) were synthesized and single
crystals were grown using slow evaporation technique. The structure of the synthesized compound was
confirmed using mass spectroscopy, 1H-NMR and FTIR spectroscopy. Single crystal X-ray structural anal-
ysis reveals that both crystals are crystallized under a monoclinic P21/n space group. C-H...O, C-H...Pi and
Received 1 May 2021
Revised 15 July 2021
Accepted 22 August 2021
Available online 25 August 2021
˚
Pi...Pi intra and intermolecular hydrogen bond interactions of compound 1 and C18-H18C...O7 (2.638 A)
Keywords:
˚
Antibacterial agent
Chalcone
and C3-H3...S1 (2.915 A) intermolecular interactions in compound 2 contributed to molecular stability.
The thiophene-chalcones analogues were screened for the in-sillico studies to understand the antibacte-
rial activity. Molecular docking study was analyzed for the compound 1 and 2 with Penicillin binding
proteins (PDB:1MWT) and Staphylocoagulase (PDB:1NU7) of MRSA. Compound 1 showed -6.0 kcal/mol
for both Penicillin binding proteins and Staphylocoagulase while compound 2 showed the binding score
-6.9 kcal/mol for 1MWT and -7.1 kcal/mol for 1NU7 protein, respectively. The crystallized compounds
were also examined for their ADMET analysis and it was observed that there was no AMES toxicity in
both compounds. Compound 1 and 2 were also showed 0.529 log mg/kg/day and 1.096 log mg/kg/day
maximum tolerated dose (human), respectively. Ultimately, molecular dynamics simulation of compound
1 and 2 confirmed the best possible interaction and stability in the active site of INU7 and allosteric site
of IMWT proteins for 20 ns.
Thiophene
Molecular docking and MD simulations
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
teresting biological activity and their versatile nature of flexible
structure [9,10]. Natural and synthetic chalcones provide a broad
Chalcones (1,3-diphenylprop-2-ene-1) are a group of organic
compounds that comprise two aromatic rings, associated with an
unsaturated ketone moiety [1,2]. Chalcones are a key group con-
taining electron donors, acceptors groups attached to aromatic
rings in various positions, that lead to change the properties
of the molecules [3]. To transform them into remarkable com-
pounds based on the formation of carbon-carbon bonds, various
methods like Claisen-Schmidt condensation [4], grinding process
[5], Suzuki coupling reaction [6], microwave irradiation [7], and
Friedel-Crafts acylation [8] can be used. Chalcones are now con-
sidered as promising lead compounds in a wide range of phar-
maceutical and medicinal chemistry applications due to their in-
variety of antimicrobial [11], anti-inflammatory [12], anticancer
[13] and antioxidant [14] properties towards human diseases. Of
late chalcones with heteroatoms have gained interest; especially
those with thiophene substituents have gotten attracted global in-
terest. Several researchers have documented chalcones with het-
eroatoms such as halogens, Sulphur and Nitrogen atoms, particu-
larly thiophene containing chalcones are reported due to their sev-
eral applications, such as antimicrobial [15], antibacterial [16], anti-
fungal [17], anti-inflammatory [18], and antimalarial [19] function.
Researchers have been interested in organic single crystals due to
their extremely sustained orientation stability and high density of
active components, as evidenced in existing literature [20]. Infor
cites of above-mentioned properties structural analysis of crystals
about to bonding properties of the atoms in a molecule, crystal
symmetry, hydrogen bond interaction and crystal packing proper-
ties are evaluated by using single crystal X-ray diffraction tech-
∗
Corresponding authors.
E-mail addresses: nanjundaswamy.s144@gmail.com (S. Nanjundaswamy),
csk@jssstuniv.in (C.S. Karthik), drmallu66@gmail.com (P. Mallu).
https://doi.org/10.1016/j.molstruc.2021.131365
0022-2860/© 2021 Elsevier B.V. All rights reserved.

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Scheme 1. Schematic representation of synthesis of tittle compounds.
nique. The application of computational approaches to the evalu-
ation of antibacterial activities against Methicillin-resistant Staphy-
lococcus aureus (MRSA) has shown tremendously useful in un-
derstanding the structures and other essential physicochemical
properties.
134.66, 132.83, 130.16, 129.02, 127.86, 121.32, 21.93, 19.84. MS (ESI)
m/z: 256.09. Elemental Analysis: Calculated: For C16 H16 SO (in %):
C:74.96, H:6.29. found: C:74.53, H:6.09.
2. Experimental
The present research work demonstrates the synthesis, charac-
terization, molecular docking and dynamic simulation studies of
novel thiophene-based chalcone derivatives. Single crystal X-ray
structural investigation leads to the identification of various in-
termolecular interactions which contribute to the protein-ligand
binding. Molecular docking studies revealed good binding scores
of novel compounds with the 1MWT and 1NU7 proteins of MRSA
bacteria and these docking results were best validated by the
molecular dynamic simulation studies.
2.1. Single crystal X-ray structure determination
Single crystal X-ray intensity data were collected at 293 K using
˚
graphite-monochromated Mo-Kα(λ=0.71073 A) radiation equipped
with Rigaku XtaLAB mini three-circle CCD diffractometer. The data
was collected with an exposure time of 3s and the scan width of
1°. The data collection strategy was planned and executed using
CrystalClear-SM Expert 2 [21]. Structure solution was carried out
using direct methods and refinement by full-matrix least-squares
against F2 using SHELXS and SHELXL-2018 [22,23] programs as im-
plemented in OLEX2 software [24]. The non-hydrogen atoms were
assigned with anisotropic displacement parameters. Crystal struc-
ture geometry calculations were carried out using the PLATON pro-
gram [25]. The ORTEP and packing diagram of both compound 1
and 2 was generated using MERCURY4.2.0 [26]. The complete crys-
tallographic data and refinement parameters are summarized in
Table 1.
1.1. Materials and method
High purity chemicals and reagents were purchased from Sigma
Aldrich (Merck Pvt. Ltd., India). The elemental analysis was ob-
tained from Perkin Elmer 2400 elemental analyzer. The FT-IR spec-
tra were recorded on a Perkin Elmer Spectrum Version 10.03.09.
The 1H NMR spectra (Agilent-NMR) were recorded using CDCl3 as
solvent at 400 MHz Chemicals shifts were reported in parts per
million relatives to TMS. A water micro TOF QII mass spectrometer
was used to determine the mass of the synthesized compounds.
2.2. Molecular docking
1.2. Synthesis of thiophene chalcones
Molecular docking studies were carried out using Auto-Dock
Vina 1.5.6 tool. It was used to demonstrate feasible docking modes
of interaction between ligand and biological targets of interest. The
3D structure of the target protein was obtained in the PDB for-
mat from the RCSB Protein Data Bank (PDB ID: 1NU7 & 1MWT).
The bounded ligand was removed by using Biovia Discovery Stu-
dio 2019. The energy of proteins was reduced using an Auto-Dock
method and polar hydrogen atoms were added [27]. In order to
identify the binding sites, the grid box was built using the grid
size of X = 17.71, Y = 55.99, Z = 44.36 for Staphylocoagulase and
X= 13.33, Y = 30.36, Z = 23.67 for PBP2a allosteric site. The 3D
structure of the compound was saved in PDB format with the Mar-
vin JS program. The binding affinity of the ligand with a unit of
kcal/mol was noted as a negative ranking. Using Biovia Discovery
Studio 2019, the protein-ligand interactions were analyzed and vi-
sualized.
A mixture of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione
(1 equivalence) and aldehydes (1 equivalence) was dissolved in
ethanol, catalytic amount of sodium ethoxide and FeONPs were
added. The reaction mixture was refluxed for 5-6 h. The comple-
tion of the reaction was espied by thin layer chromatography. After
the completion of the reaction, the reaction mixture was filtered
and poured into crushed ice, the separated solids were filtered and
recrystallized from ethanol. The synthesis of thiophene chalcones
is outlined in Scheme 1.
1.2.1. Compound 1. 3-(pyridin-4-yl)-1-(thiophen-2-yl)
prop-2-en-1-one
FT-IR (KBr, cm−1): 1654 (C=O), 1588 (C=C), 1418 (Ar, C=C), 720
(C-S). 1H NMR: (400 MHz, CDCl3) 8.72 (d, 2H, Py-H), 7.98 (d, 1H,
Ar-H), 7.80 (d, 1H, Ar-H), 7.68 (d, 1H, CH=C), 7.53 (d, 2H, Py-H),
7.11 (t,1H, Ar-H), 7.00 (d, 1H, C=CH). 13C: (400 MHz, CDCl3) 180.33,
154.75, 148.81, 143.45, 139.71, 137.02, 132.81, 130.17, 129.05, 127.07,
124.37, 122.74. MS (ESI) m/z: 215.04. Elemental Analysis: Calcu-
lated: For C12H9NOS (in %): C-66.95, H-4.21, N-6.51. Found: C-66.87,
H-4.37, N-6.40.
2.3. Molecular dynamic simulation
The MD simulations for the crystallized compound 1 and 2
were carried out against 1MWT and 1NU7, Schrodinger 2020-2
suite of Desmond modules was used to study the stability of the
receptor-ligand system. The OPLS2005 force field had been used
to simulate water molecules and evaluate the atomic interaction
with the help of the predetermined TIP3P water model technique
1.2.2. Compound 2. 3-mesityl-1-(thiophen-2-yl)prop-2-en-1-one
FT-IR (KBr, cm−1): 1647 (C=O), 1592 (C=C), 1413 (Ar, C=C),
716 (C-S). 1H NMR: (400 MHz, CDCl3) 7.88 (d, Th-H, 1H), 7.82
(d, Th-H, 1H), 7.72 (d, C=CH, 1H), 7.21(t, Th-H, 1H), 6.92 (s, Ar-H,
2H), 6.73(d, C=CH, 1H), 2.44(s, CH3, 3H), 2.32(s, CH3, 3H), 2.14(s,
CH3, 3H). 13C: (400 MHz, CDCl3) 180.31, 145.12, 139.74, 137.42,
˚
[28]. The shape and size of the repeating unit buffered at 10 A dis-
tances which were specified using cubic periodic boundary con-
ditions. Sufficient Na+ alongside salt atoms were added to bal-
ance the system charge and were randomly positioned in the sol-
2

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Table 1
Crystal structure data and refinement details of compound 1 and 2.
Parameter
Compound 1
1938902
Compound 2
CCDC deposit No.
Empirical formula
Formula weight
Temperature (K)
2075621
C12H9OS
215.27
C
16H16OS
256.36
293K
293K
˚
˚
Wavelength (A)
0.71073 A
0.71073
Crystal system, space group
Unit cell dimensions
Monoclinic, P21/n
Monoclinic, P21/n
˚
a (A)
10.794(5)
12.060(4)
5.7311(15)
15.336(6)
90
˚
b (A)
5.9290(18)
˚
c (A)
20.644(9)
α (°)
β (°)
γ (°)
90
97.81(2)
98.080
90
90
3
˚
Volume A
1308.9(9)
1049.5(6)
4
Z
4
Density(calculated) in Mg m−3
1.301
1.362
Absorption coefficient (mm−1
)
0.232
0.277
F000
544
448
θ range for data collection
3.32° to 27.61°
−7 ≤ h ≤ 13
3.41° to 27.52°
−13 ≤ h ≤ 15
−7 ≤ k ≤ 7
−19 ≤ l ≤ 10
3805
Index
ranges
−7 ≤ k ≤ 7
−26 ≤ l ≤ 22
4494
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final [I >2σ(I)]
2793 [Rint = 0.0922]
Full matrix least-squares on F 2
2793 / 0 / 166
0.975
2358 [Rint = 0.0922]
Full matrix least-squares on F 2
2358 / 0 / 136
1.068
R1 = 0.0660, wR2 = 0.1086
R1 = 0.1671, wR2 = 0.1510
0.203 and −0.240
R1 = 0.0647, wR2 = 0.1364
R1 = 0.1018, wR2 = 0.1600
0.279 and −0.335
R indices (all data)
˚
Largest diff. peak and hole e A
3
Table 2
Docking score of the compound 1, compound 2 and Vancomycin with 1NU7 and 1MWT proteins of MRSA.
Docking Score in kcal/mol
Compound
Structure
1NU7
1MWT
Compound 1
−6.0
−6.0
Compound 2
−7.1
−8.6
−6.9
−8.3
Vancomycin
3

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
vated system to nullify the system electrically. After building the
solvated system containing the protein complex with the ligand,
the compound was kept with a convergence threshold of 1 kcal
mol−1A by using the conjugate gradient algorithm. The NPT en-
˚
semble was used to run molecular dynamics simulations with spe-
cific boundary conditions [29]. The temperature and pressure were
maintained at 300 K throughout the process and subjected to a
20 ns run. Schrodinger’s maestro interface 2020-2 was used to
make all of the molecular dynamic simulation snapshots [30,31].
2.4. ADME and toxicity prediction
The standard pharmacokinetics (absorption, distribution,
metabolism and excretion) and drug-likeness were determined
for the estimation of the drug-likeness and pharmacokinetics
parameters in the field of the drug discovery process [32]. Both
the crystal structures were drawn on Marvin JS software in 2-D
structure format and converted into SMILES using Swiss-ADME
online tool (http://swissadme.ch/). The pkCSM online tool was
used for the prediction of ADMET [33]. This includes Intestinal
absorption, skin permeability, BBB permeability, CNS permeability,
renal OCT2 substrate, AMES toxicity, oral rat acute toxicity, oral rat
chronic toxicity and skin sensitization.
3. Results and discussions
3.1. Chemistry
The structure of the synthesized chalcone analogues were cor-
roborated based on spectral techniques such as FT-IR, 1H-NMR, and
mass spectrometry. The structure and physical data of analogues
are depicted in Table 2. Theoretically, values and experimentally
determined values of elemental analysis lies within
0.4 %. The
FT-IR spectra of synthesized two chalcones were recorded using
KBr pellets in the range of 4000-400 cm−1. There is a strong, broad
absorption band that appeared at 1654 and 1647 cm−1 were as-
signed to the C=O. The absorption bands at 1588 & 1592 cm−1 are
due to the presence of C=C stretch. The absorption band at 720 &
716 cm−1 is due to the C-S stretch in synthesized compounds.
The 1H NMR spectra for the synthesized chalcones were
recorded using CDCl3. Their peak multiplicity and integration as-
signed the expected resonances. The spectral integration shows
good accordance with the synthesized chalcones. The 1H NMR
spectral data of aldehyde proton (-CHO) around δ10.0 ppm is ab-
sent in the spectra of all synthesized compounds, which confirms
the formation of α, β-unsaturated compounds (Chalcones). The
proton spectral data following with respect to the number of pro-
tons and their chemical shifts with the proposed structures. The
synthesized chalcones were further confirmed by the existence of
a molecular ion peak in mass spectra. Mass spectra of the synthe-
sized compounds showed an M+ fragmentation peak in agreement
with their molecular formula. The mass spectra of compound 1
showed molecular ion peak at m/z 215.04 which is in accord with
the molecular formula C12H9NOS, and mass spectra of compound 2
showed molecular ion peak at m/z 256.09 which is in accord with
the molecular formula C16 H16 SO, Fig. 1 illustrates the mass spectra
of compounds 1 and 2.
Fig. 1. Mass spectra of both compound 1 and 2.
compound 2 has coplanar structure. ORTEP of the molecule’s com-
pound 1 and 2 with thermal ellipsoids drawn at 50% probabil-
ity are shown in Fig. 2. The crystallographic information of the
molecules is given in Table 1. Bond lengths, bond angles, and tor-
sional angles of both compound 1 and 2 are given in supplemen-
tary Tables S1 and S2.
The crystal structures of compound 1 and 2 are stabilized by
various types of inter and intramolecular interactions.
3.2. Crystal growth and XRD
Methyl group of compound 2 played a major role in stabiliz-
ing the crystal structure by forming intermolecular hydrogen bond
interactions. C18 atom of compound 2 formed hydrogen bond in-
teraction with the Oxygen atom of the adjacent molecule with
Single crystals of both compound 1 and 2 were grown by a
slow evaporation method using methanol solvent. Both compound
1 and 2 were crystallized in the monoclinic P 21/n space group,
confirmed by the single crystal x-ray diffraction study. The molec-
ular structure of compound 1 is significantly non-planar whereas
˚
the donor-acceptor distance of 2.63 A and Hydrogen atoms of the
methyl group interacted with the adjacent molecules to form two
˚
different short interactions with a distance of 2.33 A. All these
4

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 2. ORTEP of compound 1 and 2 with thermal ellipsoids are drawn at 50% probability.
three interactions of compound 2 combine to form a supramolec-
ular synthon along the crystallographic ab-plane shown in Fig. 3.
˚
˚
C16-H16A...C13 (2.838 A), C18-H18C...O7 (2.638 A), C4-H4...O7
˚
˚
(2.658 A), and C3-H3...S1 (2.915 A) intermolecular interactions in
compound 2 contributed to molecular stability by constructing
three supramolecular R22(13), R21(11) and R22(8) ring motifs Fig. 4.
C-H...π interaction between the methyl group and the centroid of
˚
thiophene ring with a distance of 2.98 A and Pi...Pi interaction be-
˚
tween thiophene rings with a distance of 4.88 A of the adjacent
molecules are also played a key role in stabilizing the crystal struc-
ture of compound 2 shown in Fig. 5.
Crystal structure of compound 1 exhibits C-H...O intra and inter-
molecular hydrogen bond interactions, C-H...Pi, C-O...Pi and Pi...Pi
interactions greatly contribute to the formation of crystal packing
and molecular stability of compound 1. C9-H9...O7 intramolecu-
˚
˚
lar hydrogen bond interaction [D-H: 0.93 A, H...A: 2.49 A, D...A:
˚
2.822(4) A and D-H...A: 101°] form the S(5) ring motif whereas,
˚
C9-H9...O7 intermolecular hydrogen bond interaction [D-H: 0.93 A,
˚
˚
H...A: 2.58 A, D...A: 2.3.392(4) A, D-H...A: 146° and symmetry code:
1-x, 2-y,-z] lead to the formation of R22(10) supramolecular ring
motif. These two intra and intermolecular hydrogen bond interac-
tions combined to form four membered R22(4) parallelogram ring
motifs along crystallographic axes (Fig. 6). C2-H2...N13 and C15-
H15...O7 interactions joined to construct a supramolecular R44(20)
synthon along b-axis (Fig. 4). C12-H12...Cg2 intermolecular interac-
tions contributed to the crystal structure packing of compound 1
Fig. 3. Supramolecular synthon of compound 2along crystallographic ab-plane.
5

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 4. Various supramolecular ring motifs of compound 1 and 2 formed by intermolecular hydrogen bond interactions.
˚
central coagulation zymogen, prothrombin, conformationally dur-
ing host infection, thereby activating the cleavage of fibrinogen to
fibrin. This model explains the coagulant properties and efficient
fibrinogen by coagulase enzyme [34]. S. aureus, susceptible to β-
lactam antibiotics owing to the irreversible acylation of the active
site serine by the β-lactam antibiotics, the transpeptidase function
of PBP2a is lost. PBP2a inhibition leads to abnormalities such as
elongation, lesions, loss of selective permeability, and subsequent
cell death and lysis in the structure of the cell wall. Also, MRSA be-
with the H...Cg and O...Cg distance of 2.91 and 3.687(3) A, respec-
tively, where Cg2 is the centroid of the pyridine ring (Fig. 7).
3.3. Molecular docking
The molecular docking study of synthesized compounds with
MRSA proteins (PDB ID 1NU7 & 1MWT) was investigated. Staphy-
lococci coagulase-positive from S. aureus is a very well-known
pathogen that can cause several infections. Coagulase triggers the
6

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 5. C-H...π interaction between methyl group and the centroid of thiophene ring (a) and Pi...Pi interaction between thiophene rings (b) of compound 2.
Fig. 6. Intra and intermolecular hydrogen bond interactions of compound 1 leads to formation of different graph set descriptors.
comes immune to β-lactam acylation due to the presence of PBP2a
and successfully catalyzes the DD-transpeptidation reaction, which
is essential to accomplish cell wall formation. PBP2a is therefore
considered a prime candidate for inhibition of MRSA. To analyze
the difference in binding efficiency of compound 1 and 2 against
the allosteric site of PBP2a, molecular docking analysis was carried
out.
The binding component of the compound was found to be
present in the active binding sites. Compound 1 binds to pro-
tein residues of LYS145, THR147 GLY219, CYS191, GLU217 and
so on of 1NU7 protein, the close contact of pyridine ring with
˚
THR147 amino acid residue with distance 2.09 A through hydrogen
bond interaction, and oxygen of carbonyl group make interaction
˚
through hydrogen bonding with GLY219 with distance 2.59 A was
observed in compound 1, and HIS583, SER403, ASN464, GLU294,
TYR272, LYS273 and so on of allosteric site of the 1MWT protein
with varying forms of interaction. Oxygen of carbonyl group make
interaction through hydrogen bonding with LYS273 with distance
˚
2.13 A was observed in compound 1, The compound 1 showed
a docking score of -6.0 kcal/mol with 1NU7 coagulase protein
and -6.3 kcal/mol and -6.0 kcal/mol with 1MWT allosteric site of
the protein. Compound 2 is found to exhibit the docking score
of -7.1 kcal/mol with 1NU7 coagulase protein and a score of -
6.9 kcal/mol at the active and allosteric site of the 1MWT protein.
Fig. 7. C-H...π Intermolecular interactions contributed to the crystal structure pack-
ing of compound 1.
7

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 8. Protein ligand complex of compound 1 with active site of 1NU7 (a & b), molecular docking 2D interaction of compound 1 (c), and interaction inside the binding
pocket (d). Protein ligand complex of compound 2 with active site of 1NU7 (e & f): molecular docking 2D interaction of compound 2 (g), and interaction inside the binding
pocket of protein (h).
Compound 2 is found to exhibit interaction with various amino
acids like LEU99, CYS42, HIS57, ALA642, SER462, VAL256, and so
on of 1NU7 and an allosteric site of 1MWT protein. The dock-
ing interaction images of compound 1, compound 2, and Van-
comycin are illustrated in Figs. 8–10. Here in our study compound
2 being the potent antibacterial agent against 1NU7 and 1MWT
proteins, displayed the score of -7.1 and -6.9 kcal/mol which is
comparable to the standard drug vancomycin with the score of
-8.6 and -8.3 kcal/mol, respectively. The docking scores for the
tested compounds revealed that synthesized admixtures could in-
teract with one or more amino acids in the receptor’s binding
pocket. The docking results and specific interactions (bond length
8

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 9. Protein ligand complex of compound 1 with allosteric site of 1MWT (a & b), molecular docking 2D interaction of compound 1 (c), and interaction inside the binding
pocket (d). Protein ligand complex of compound 2 with allosteric site of 1MWT (e & f), molecular docking 2D interaction of compound 2 (g), and interaction inside the
binding pocket of protein (h).
and docking energies) in the binding phase are shown in Tables 2
and 3.
dicting stronger ligand-receptor interactions after docking studies,
and so on [35]. In the present investigation the root mean square
deviation (RMSD), the root mean square fluctuation (RMSF) anal-
ysis of various interactions, and percentage of hydrogen bond for-
mation compound 1 & 2 with Staphylocoagulase (1NU7) and PBP2a
(1MWT) proteins. According to docking interaction, RMSD revealed
compound 1 with 1NU7 produced excellent interaction and dock-
3.4. Molecular dynamic simulation
MD simulation was used to investigate confirmative stability,
structural model alterations, internal movements, scoring and pre-
9

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 10. Protein ligand complex of vancomycin with the allosteric site of 1MWT (a & b) and interaction inside the binding pocket (c). Protein ligand complex of vancomycin
with active site of 1NU7 (d & e) and interaction inside the binding pocket of protein (f).
10

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Table 3
Specific interaction of synthesized compound 1, 2 and Vancomycin with 1NU7 and 1MWT protein of MRSA.
Distance
˚
Protein PDB ID
Compound
Residue involved
Ligand
Interaction type
(A)
1NU7
Compound 1
THR147
GLY219
THR147
LYS 145
CYS191
GLU192
TRP215
GLY216
N of Pyridine
O of Carbonyl
group
Hydrogen
2.09
2.59
3.68
3.78
3.84
4.29
4.61
4.99
Hydrogen
Carbon
C of Pyridine
C of Pyridine
π of Thiophene
π of Pyridine
π of Thiophene
π of Thiophene
O of Carbonyl
group
Carbon
Amide π stacked
π Anion
Amide π stacked
Amide π stacked
Compound 2
Vancomycin
Compound 1
Compound 2
SER195
TYR60A
HIS57
Hydrogen
π sigma
π sigma
π sigma
π alkyl
π sulfur
Alkyl
2.36
3.63
3.84
3.91
4.12
4.72
5.00
CH3 group
CH3 group
π of Benzene
CH3 group
S of Thiophene
CH3 group
Oxygen
LEU99
TRP60D
HIS57
LEU99
LYS78
Hydrogen
Hydrogen
Hydrogen
Hydrogen
Hydrogen
Hydrogen
Hydrogen
Alkyl
2.13
2.28
2.47
2.53
2.61
2.70
3.04
3.93
2.13
2.71
3.11
3.91
3.95
5.02
ASP5
Hydrogen
SER7
Oxygen
ASP221A
SER7
Hydrogen
Oxygen
LYS78
Oxygen
CYS220
LYS8
Hydrogen
Carbon
1MWT (Allosteric site)
LYS273
ASP295
TYR272
ASP275
TYR272
LYS273
O of Carbonyl
group
Hydrogen
π Donor
Carbon
π of Pyridine
O of Carbonyl
group
π Anion
π sulfur
π alkyl
π of Pyridine
S of Thiophene
π of Pyridine
O of Carbonyl
group
SER240
VAL277
VAL277
PRO258
MET372
VAL256
HIS293
TYR373
ARG151
ARG241
Carbon
π sigma
Alkyl
3.59
3.70
4.67
4.74
4.87
5.00
5.00
5.01
5.03
5.06
π of Thiophene
CH3 group
CH3 group
CH3 group
CH3 group
S of Thiophene
π of Benzene
π of Thiophene
π of Thiophene
Oxygen
Alkyl
Alkyl
Alkyl
π sulfur
π-π T shaped
π alkyl
π alkyl
Vancomycin
LYS148
THR238
LYS148
THR216
VAL277
Hydrogen
Hydrogen
Hydrogen
Hydrogen
Alkyl
1.93
2.52
2.64
2.67
3.79
Hydrogen
Oxygen
Oxygen
Carbon
ꢀ
ing results with both Staphylocoagulase (1NU7) and PBP2a (1MWT)
an H-bonding interaction of up to 0.04 with 1NU7 s ARG221 and
SER195 amino acids, while compound 2 had an H-bonding interac-
tion of up to 0.03 with TRP60 and LYS60 amino acids. Water bridge
bonding and hydrophobic bonds were visible in the remaining ar-
eas. Frequent direct H-bonds of compound 1 were observed with
residues GLU192, GLU146, and HIS57, respectively. Similarly, com-
pound 2 had 61% interaction with the HIS57. However, both the re-
sults were found to be converging after 20 ns of simulated time it
can be concluded that compound 2 had greater interaction stabil-
ity with active amino acids of 1NU7 than compound 1. Fig. 11 and
12 reveal RMSD, RMSF, protein-ligand contacts, and ligand-protein
contacts of compound 1 and 2 with 1NU7 and 1MWT protein, re-
spectively.
˚
proteins. Compound 1 had a strong interaction up to 9 ns (0.7 A to
˚
3.2 A) with 1NU7; this gradually decreased up to 20 ns, while com-
˚
˚
pound 2 showed a moderate interaction up to 9 ns (0.6 A to 3.8 A),
˚
˚
low interaction up to 10–17.5 ns (2.0 A to 4.0 A) and it showed
˚
˚
a good interaction up to 17.5–20 ns (3.0 A to 4.2 A) with 1NU7
as shown in Fig. 11. The RMSF graph of compound 1 showed that
the significant peaks of fluctuations have been observed initially,
˚
residue number 380 up to 4.8 A, residues between 430 and 490
˚
˚
with up to 2.1 A, residues number 550 up to 2.8 A and residues
˚
number 290 up to 5 A get the maximum deviation. While RMSF
graph of compound 2 showed that residues number 310 up to
˚
˚
4.0 A, residues number 550 up to 4.8 A, residue number 290 and
˚
380 up to 6.4 A get the maximum deviation throughout the MD
RMSD of compound 1 with 1MWT protein had a low interac-
˚
˚
simulations. The remaining residues were known to be moder-
tion up to 10 ns (1.9 A to 5.4 A) with 1MWT and subsequently
showed a good interaction up to 20 ns, while compound 2 showed
˚
ately stable and fluctuating well below 2.0 A. Compound 1 had
11

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 11. Illustration to show the outcomes of molecular dynamic simulation of Compound 1 and 2 complexes. RMSD, RMSF of the backbone over the 20 ns MDS at 300 K of
the complexes systems. Protein (1NU7) ligand interaction (P-L contacts) & 2D- Diagram of Ligand Protein (L-P Contacts) interaction.
˚
˚
MD simulations. The remaining residues were known to be mod-
a moderate interaction up to 20 ns (1.6 A to 6.4 A) with the 1MWT.
The significant peaks of compound 1are fluctuated have been ob-
served from the RMSF graph, initially, residue number 10–50 over
˚
erately stable and fluctuating well below 2.0 A. Compound 1 had
an H-bonding interaction of up to 0.04 with SER643 and ALA642
amino acids, while compound 2 had an H-bonding interaction of
up to 0.08 with SER403, LYS597, and SER598 amino acids. Water
bridge bonding and hydrophobic bonds were visible in the remain-
ing areas. Frequent direct H-bonds of compound 1 were observed
with residues ALA146, and HIS57, respectively. Similarly, compound
2 had 81% and 47% interaction with the HIS583 along with 31% in-
˚
˚
4.2 A, residues number 60 and 180 up to 4.7 A, residues number
˚
˚
360 up to 3.7 A, and residues number 290 up to 4.9 A get the
maximum deviation. While RMSF graph of compound 2 showed
˚
that residues number 70 and 90 up to 5.1 A, residues number 280
˚
˚
up to 6 A, residue number 200 and 240 up to 4.1 A, and residues
˚
number 180 up to 7 A, get the maximum deviation throughout the
12

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 12. Illustration to show the outcomes of Molecular dynamic simulation of Compound 1 and 2 complexes. RMSD, RMSF of the backbone over the 20 ns MDS at 300 k of
the complexes systems. Protein (1MWT) ligand interaction (P-L contacts) & 2D- Diagram of Ligand Protein (L-P Contacts) interaction.
teraction with LYS597. Hence it can be concluded that compound
2 had greater interaction stability with amino acids of 1MWT than
compound 1.
the drug discovery and development process which consumes less
time. The ADMET results of both compounds have been interpreted
using pkCSM tool. The compounds show excellent gastrointestinal
absorption and also a low skin permeability (log Kp > -2.5). The
compound exhibit properties such as P-glycoprotein substrate in-
hibitor (I and II), cytochrome P450 enzyme inhibitor are shown in
Table 4. Compound 2 reveals a high value of log VDss. Both the
compounds are readily cross the blood brain-barrier and penetrate
3.5. ADMET and toxicity predictions
ADMET properties were predicted to evaluate potential lead
candidate. Toxicity prediction is one of the important methods of
13

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Fig. 13. (a) Bioavailability radar and (b) Boiled-Egg image of compound 1 and 2.
the central nervous system. Both compounds are not likely to be
renal OCT2 substrates. Both compounds are not showing an AMES
toxic nature and also compounds reveal a high maximum toler-
ated dose for human. The oral rat acute and chronic toxicity were
also studied and results have been interpreted. Hepatotoxicity and
skin sensitization of both compounds were studied and results are
shown in Table 4. In Minnow toxicity compound 2 is regarded as
high acute toxicity. Both compounds obey all the 5 rules of drug-
likeness including Lipinski, Ghose, Veber, Egan, and Muegge rules
and the results were depicted in Table 5. Boiled-egg model of com-
pounds 1 and 2 are shown in Fig. 13.
ADMET study of vancomycin revealed that it has poor gastroin-
testinal absorption and low skin permeability (log Kp > -2.5), low
value of log VDss (log VDss < -0.15), inhibitors of cytochrome P450
enzyme, vancomycin, does not obey all the five rules of druglike-
ness including Lipinski, Ghose, Veber, Egan and Muegge rules. AD-
MET results of vancomycin was depicted in supplementary Tables
S3 and S4 and boiled-egg model of vancomycin shown in Fig. S1.
14

S. Nanjundaswamy, Gurumallappa, M.K. Hema et al.
Journal of Molecular Structure 1247 (2022) 131365
Table 4
ADME and Toxicity by using pkCSM tool.
Parameters
Compound 1
Compound 2
Absorption
Water solubility (log mol/L)
-2.79
1.882
96.27
-1.872
No
-5.564
1.255
95.595
-2.069
Yes
Caco2 permeability (log Papp in 10−6 cm/s)
Intestinal absorption (human) (% Absorbed)
Skin Permeability (log Kp)
P-glycoprotein substrate
P-glycoprotein I inhibitor
P-glycoprotein II inhibitor
VDss (human) (log L/kg)
Fraction unbound (human) (Fu)
BBB permeability (log BB)
CNS permeability (log PS)
CYP2D6 substrate
No
No
No
No
Distribution
Metabolism
-0.026
0.187
0.096
-1.639
No
0.576
0
0.498
-1.319
No
CYP3A4 substrate
No
Yes
CYP1A2 inhibitior
Yes
Yes
CYP2C19 inhibitior
Yes
Yes
CYP2C9 inhibitior
Yes
Yes
CYP2D6 inhibitior
No
No
CYP3A4 inhibitior
No
No
Excretion
Toxicity
Total Clearance (log ml/min/kg)
Renal OCT2 substrate
0.015
No
-0.105
No
AMES toxicity
No
No
Max. tolerated dose (human) (log mg/kg/day)
hERG I inhibitor
0.529
No
1.096
No
hERG II inhibitor
No
No
Oral Rat Acute Toxicity (LD50) (mol/kg)
Oral Rat Chronic Toxicity (LOAEL) (log mg/kg_bw/day)
Hepatotoxicity
2.1
2.164
1.11
Yes
2.104
No
Skin Sensitization
Yes
No
T. Pyriformis toxicity (log ug/L)
Minnow toxicity (log mM)
1.343
0.46
1.879
-0.743
Table 5
Druglikeness by using Swiss-ADME tool.
Jothi Ramalingam: Writing - review and editing. N. K. Lokanath:
Writing - review and editing. P Mallu: Supervision, Writing - re-
view and editing.
Drug likeness
Compound 1
Compound 2
Lipinski
Ghose
Yes
Yes
Yes
Yes
Yes
0
Yes
Yes
Yes
Yes
Yes
0
Declaration of Competing Interest
Veber
Egan
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Muegge
Violations
Acknowledgment
4. Conclusion
The authors are thankful to SJCE, JSS Science and Technology
University for providing supercomputing facility and VGST-CISEE
Project (GRD 647), GOK, Karnataka, The author (R. J) express thank-
ful and financial support by the Researchers Supporting Project
Number (RSP-2021/354) King Saud University, Riyad, Saudi Arabia.
In the present investigation, new thiophene chalcones were
synthesized and characterized by 1H-NMR and IR spectroscopic
techniques. The single crystal structures of thiophene chal-
cones were elucidated by X-ray diffraction study. In the crystal
structure of 3-(3pyridine-4-yl)-1-(thiophen-2-yl)prop-2-en-1-one
and 3-mesityl-1-(thiophen-2-yl)prop-2-en-1-one, the molecules
are connected via C-H…O and C3-H3…S1 hydrogen bonds which
are greatly contributed to molecular stability. Molecular docking
and molecular dynamics simulation studies revealed the inter-
action mode, binding energy, existence of hydrogen bonds, hy-
drophobic interactions and stability of protein-ligand complexes
upto 20 ns simulation run. From the present investigation com-
pound 2 showed a promising antibacterial activity against MRSA
which can be develop as an antibacterial agent in futuristic stud-
ies.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131365.
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