Synthesis, molecular docking, and in silico ADMET studies of 4-benzyl-1-(2,4,6-trimethyl-benzyl)-piperidine: Potential Inhibitor of SARS-CoV2

Article abstract of DOI:10.1016/j.bioorg.2021.104967

Nowadays, over 200 countries face a wellbeing emergency because of epidemiological disease COVID-19 caused by the SARS-CoV-2 virus. It will cause a very high effect on the world's economy and the worldwide health sector. The present work is an investigati

Full text of DOI:10.1016/j.bioorg.2021.104967

Bioorganic Chemistry 112 (2021) 104967
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis, molecular docking, and in silico ADMET studies of 4-ben-
zyl-1-(2,4,6-trimethyl-benzyl)-piperidine: Potential Inhibitor of SARS-CoV2
,
R. Nandini Ashaa, B. Ravindran Durai Nayagama *, Nattamai Bhuvaneshb
a Department of Chemistry and Research Centre, Pope’s College (Autonomous), Sawyerpuram-628251, Affiliated to Manonmaniam Sundaranar University, Tirunelveli
627012, Tamil Nadu, India
b Department of Chemistry, Texas A&M University, College Station, TX 77842, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Nowadays, over 200 countries face a wellbeing emergency because of epidemiological disease COVID-19 caused
by the SARS-CoV-2 virus. It will cause a very high effect on the world’s economy and the worldwide health
sector. The present work is an investigation of the newly synthesized 4-benzyl-1-(2,4,6-trimethyl-benzyl)-piper-
idine (M1BZP) molecule’s inhibitory potential against important protein targets of SARS-CoV-2 using compu-
tational approaches. M1BZP crystallizes in monoclinic type with P1211 space group. For the title compound
M1BZP, spectroscopic characterization like 1H NMR, 13C NMR, FTIR, were carried out. The geometry of the
compound had been optimized by the DFT method and its results were compared with the X-ray diffraction data.
The calculated energies for the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Mo-
lecular Orbital (LUMO) showed the stability and reactivity of the title compound. Intermolecular interactions in
the crystal network were determined using Hirshfeld surface analyses. The molecular electrostatic potential
(MEP) picture was drawn using the same level of theory to visualize the chemical reactivity and charge distri-
bution on the molecule. Molecular docking study performed for the synthesized compound revealed an efficient
interaction with the COVID-19 protease and resulted in good activities. We hope the present study would help
workers in the field to develop potential vaccines and therapeutics against the novel coronavirus. Virtual ADME
studies were carried out as well and a relationship between biological, electronic, and physicochemical quali-
fications of the target compound was determined. Toxicity prediction by computational technique for the title
compound was also carried out.
SARS-COV2
ADME studies
Crystal structure
DFT
Molecular docking
1. Introduction
homologous and non-homologous recombination, which expands their
host range and facilitates the crossing of species barriers [3]. Corona-
The recently declared global emergency following the outbreak of
COVID-19 has raised awareness of tackling the disease with more
effective therapeutic means. Coronavirus Disease-2019 (COVID-19) is a
respiratory disease caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) which is a novel single-stranded RNA virus
of the Coronaviridae family [1]. Although the SARS-CoV-2 virus pri-
marily affects the respiratory system, other organ systems are also
involved. Lower respiratory tract infection related symptoms including
fever, dry cough, and dyspnea were reported. It is now widely recog-
nized that respiratory symptoms of COVID-19 are extremely heteroge-
neous, ranging from minimal symptoms to significant hypoxia with
ARDS [2]. Being RNA viruses, CoVs readily evolve by mutation and
viruses are spherical in shape. Their most prominent feature is club-like
projections on the virus surface which are referred to as “spikes”. Human
coronaviruses are positive-sense RNA (30 kb) viruses. Two types of
proteins characterize HCoVs, structural protein [spike (S), envelope (E),
membrane (M), nucleocapsid (N)], and non-structural proteins (nsp1 up
to nsp16) including the RNA dependent RNA polymerase [4,5]. Among
non-structural proteins, nsp12 (RNA-dependent RNA polymerase-RdRp)
is important in the replication and transcription of the viral genome [6].
For SARS-CoV and SARS-CoV2, the S protein is the primary determinant
for host tropism and pathogenicity. It is the main target for neutralizing
antibodies and therefore of great interest in terms of immunological
response and vaccine design [7]. When we set our sights on the broad-
* Corresponding author.
E-mail addresses: nandiniasha123@gmail.com (R. Nandini Asha), b_ravidurai@yahoo.com (B. Ravindran Durai Nayagam), n_bhuvanesh@exchange.tamu.edu
(N. Bhuvanesh).
https://doi.org/10.1016/j.bioorg.2021.104967
Received 22 January 2021; Received in revised form 21 April 2021; Accepted 1 May 2021
Available online 5 May 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
spectrum antiviral drugs, we found that a drug unlisted, Remdesivir, has
demonstrated strength in trials related to MERS-CoV and Ebola virus
infection. In the United States, the first patient with COVID-19 has
shown significant improvement in clinical symptoms within 24 h of
treatment with Remdesivir [8-10]. This case has convinced the public
that Remdesivir could become a new “specific drug” for COVID-19.
Because of the urgency and current need, scientists are involved in
reusing already approved drug candidates to test in COVID-19 patients.
This is carried out to reduce cost, time, and also the risks involved in the
drug development process. No drug or vaccine has been approved yet.
Pei Liu et al identified several N-substituted compounds as potent SARS-
CoV-2 3C-like protease inhibitors [11]. Sathiskumar et al tested several
coumarin analogues as an inhibitor of SARS-CoV-2 [12].
2.3. Synthesis of 4-benzyl-1-(2,4,6-trimethyl-benzyl)-piperidine
(M1BZP)
Dissolve 2-bromomethylmesitylene and 4-benzyl piperidine (1:1)
was dissolved separately in methanol, and heated at 80 ◦C, and stirred
continuously for 1 h. The solid was filtered and vacuum-dried (Scheme
1). The dried solid was recrystallized using chloroform. Single crystal of
M1BZP formed in the solution has a single spot in TLC (Rf 0.60) in silica
gel and chloroform: acetone (70:30%v/v) eluent. The qualitative anal-
ysis confirmed the absence of bromide and the presence of nitrogen. The
yield was 85% with m.pt. 47–49 ◦C. FTIR (KBr, cmꢀ 1) (Fig.S1): 3722,
1
3026, 2905, 2745, 1941, 1868, 1442, 1388,1263, 696. H-NMR (300
MHz, DMSO-d6, δ) (Fig.S2): 1.47–1.94 (m, piperidine-H), 2.17–2.26
(s,9H), 3.31 (s,2H), 6.77–7.27 (m, Aromatic-H). 13C NMR (100 MHz,
DMSO-d6) (Fig.S3): 20.12, 20.98, 30.21, 42.93, 52.27, 59.11,
126.13–140.85 (Aromatic-C). The recorded single crystal XRD data were
deposited in CCDC, no.:1951658.
Computer-aided drug design technology minimizes wastage of time
and financial burden in the drug discovery process. Research in the
pharmaceutical industry has shown a great increase and progress in
modern computational medicinal chemistry [13]. Also, pharmacody-
namic (potency, affinity, efficacy, and selectivity), pharmacokinetic
(ADME: absorption, distribution, metabolism, and excretion), and
toxicity data of molecules can be evaluated and analysed using that
technology [14]. As a result, all these methods contribute to an efficient
and selective drug discovery process [15]. In this study, we report the
synthesis of the title compound M1BZP and single crystal XRD structural
investigation supported by various spectroscopic characterization
techniques (1H NMR, 13C NMR, FT-IR) which is validated by DFT
analysis. HOMO and LUMO, Mulliken charges, and MEP of the title
compound were also accounted. Further M1BZP is evaluated for its
potential against COVID-19 proteins through molecular docking. Based
on the ligand docking technique, inhibition against the SARS-CoV-2
virus proteins is concluded. The drug-likeness and Toxicity screening
of M1BZP were screened based on ADMET properties.
2.4. DFT studies
To procure an in-depth knowledge about the physical and chemical
properties of the above investigated crystal structure, density functional
theory (DFT) calculations were performed using a 6–311 + G(d,p) basis
set by GAMESS (US) software [23]. The molecular orbital structures and
molecular electrostatic potential diagram are visualized using Jmol
14.30.2 [24].
2.5. Hirshfeld surface analysis
The molecular Hirshfeld surfaces analysis was carried out to validate
the various types of noncovalent interaction present in the crystal
structure and their 2D fingerprint plots (FPs) were generated using
CrystalExplorer 17.5 [25] software.
2. Experimental
2.1. Materials and methods
2.6. Molecular docking studies
All the chemicals and solvents were acquired from commercial
sources with high purity and analar grade. Melting points were obtained
in open capillaries on a Gallen Kemp melting point apparatus (Sanyo).
Pre-coated silica gel plates (silica gel 0.25 mm, 60 G F 254; Merck,
Germany) were used for thin-layer chromatography and chloroform/
acetone (9.5:0.5 mL) mixture for developing solvent system. The IR
spectra were obtained in KBr discs using JASCO 4600 (Japan) spec-
trometer.1H and 13C NMR spectra (in DMSO‑d6) were recorded on
Bruker Avance III, 400 MHz, 9.4 Tesla superconducting magnet using
DMSO as a solvent. Single crystals obtained were characterized using a
BRUKER Quest X-ray (fixed-Chi geometry) diffractometer. The goni-
ometer was controlled using the APEX3 software suite [16]. The ab-
sorption correction program SADABS [17] was employed to correct the
data for absorption effects. A solution was obtained readily using XT/XS
in APEX3. The absence of additional symmetry and voids was confirmed
using PLATON (ADDSYM) [18-20]. The structure was refined (weighted
least-squares refinement on F2) to convergence. Olex 2 was employed for
the final data presentation and structure plots [21].
To verify the binding effect of the title compound (ligand) with
COVID-19 proteins, molecular docking technology was performed. MGL
tools 1.5.6 with AutoDock Vina were used for the molecular docking
analysis to detect the preferred binding sites [26,27]. From the Protein
Data Bank, three-dimensional structure of viral proteins Spike receptor
protein (2AJF), Papin-like protease (PLpro) (PDB ID: 4OVZ), Spike
glycoprotein with ACE2 receptor (PDB ID: 6ACD), Main protease (PDB
ID:6LU7), RNA dependent RNA polymerase (PDB ID:6M71), spike
binding domain with ACE2 receptor (PDB ID:6MOJ), Spike glycol pro-
tein (PDB ID:6VSB) and SARS-CoV Main protease (PDB ID:6Y84) were
downloaded in PDB format. The docking simulations were performed
with AutoDock Vina by the developer command script. The interactions
in the ligand–protein complex were visualized and analyzed using Bio-
via Discovery Studio 2020 client [28].
2.7. ADME and Toxicity prediction
Physiochemical properties of M1BZP were calculated using Osiris
data warrior software. The ADME properties (adsorption, distribution,
metabolism, and excretion) of M1BZP were predicted using Swiss ADME
online software [29]. The chemical structure of M1BZP is drawn on
Marvin to generate SMILES and inserted directly on the webpage to
initiate the prediction process. The SMILES of the compound were
submitted to the website and toxicity mode was selected [30].
2.2. Synthesis of 2-bromomethylmesitylene (M1)
Mesitylene (12.0 g, 0.10 mol), paraformaldehyde (3.08 g, 0.10 mol),
50 mL of glacial acetic acid, and 20 mL of 31 wt% HBr/acetic acid so-
lutions were stirred at 80 ◦C. After 2 h, the reaction mixture was poured
into 100 mL of water. The product 2-bromomethyl mesitylene was
filtered and vacuum-dried at room temperature [22].
3. Results and discussion
3.1. Spectral characterization
The IR spectrum of M1BZP is given in Fig. S1. A peak at 3722 cmꢀ 1 is
2

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
Scheme 1. Synthesis of M1BZP.
assigned for the polymorphism of M1BZP due to the sp3C-N and sp3C-
sp2C rotation. Absorption around 3300–2900 cmꢀ 1 is assigned to sp3C-
H, sp2CH stretch, and overtones. A weak abortion around 1735 cmꢀ 1
Table 1
Crystal data and structure refinement for M1BZP.
Identification code
m1bzpa
–
may be assigned for partial C N for resonance. Peaks around
–
1600–1400 cmꢀ 1 are for aromatic C C stretching, N H band, and
–
–
–
Empirical formula
Formula weight
Temperature
C22 H29 N
307.46
sp2CH overtones. A peak at 2745 cmꢀ 1 may be assigned for the hyper-
conjugation in mesitylene-sp3CH-N piperidine by donating the lone pair
of electrons in the nitrogen to the sp3 bridging carbon between mesi-
tylene and piperidine as the former is an electron withdrawing group, N
is the good electron donor and sp3 is a medium of electron through in-
110.0 K
Wavelength
0.71073 Å
Monoclinic
P 1 21 1
Crystal system
Space group
Unit cell dimensions
a = 10.1081(4) Å
b = 5.5022(2) Å
α
= 90◦.
duction. Absorption at 1263 cmꢀ 1 is for C N stretching. Thus M1BZP is
β = 96.6350
–
(10)◦.
a molecular crystal with polymorphism through single bond rotation
and resonance through hyperconjugation and induction.
c = 16.2450(7) Å
897.44(6) Å3
γ = 90◦.
Volume
The H1 NMR spectrum of M1BZP (fig. S2) has eleven signals. Singlet
signals at 2.17 and 2.26 ppm are assigned to the hydrogen atoms in one
and two methyl groups in the mesitylene ring. The methylene (–CH2-)
group attached to the nitrogen atom is deshielded and the signal appears
at 3.31 ppm as a singlet. All the hydrogen atoms in the piperidine ring
occur between 1.47 and 1.94 ppm. The signals for the aromatic
hydrogen atoms present in M1BZP appear between 6.77 and 7.27 ppm in
the downfield. The 13C NMR spectrum of M1BZP (fig. S3) has nearly
fifteen signals. The three aliphatic methyl carbon atoms in the mesity-
lene ring show signals at 20.12 and 20.98 ppm. Eight signals for the
aromatic carbon atoms appear between 126.13 and 140.85 ppm in the
downfield.
Z
2
Density (calculated)
Absorption coefficient
F(000)
1.138 Mg/m3
0.065 mmꢀ 1
336
Crystal size
0.483 × 0.416 × 0.059 mm3
2.262 to 24.997◦.
ꢀ 12≤h≤12, ꢀ 6≤k≤6,
ꢀ 19≤l≤19
Theta range for data collection
Index ranges
Reflections collected
21,462
Independent reflections
Completeness to theta = 24.997◦
Absorption correction
3160 [R(int) = 0.0661]
99.8%
Semi-empirical from
equivalents
Max. and min. transmission
Refinement method
0.7456 and 0.3105
Full-matrix least-squares on
F2
Data / restraints / parameters
Goodness-of-fit on F2
3160 / 1 / 212
1.041
3.2. Crystal growth and XRD
Final R indices [I greater than
2sigma(I)]
R1 = 0.0599, wR2 = 0.1593
Single crystal X-ray structural analysis confirmed that the M1BZP is
crystallized in a monoclinic P 1 21 1 space group with two independent
molecules in its unit cell (Z = 2). Fig. 1 emphasizes the thermal ellipsoid
of the title compound. Structural and bond parameter values are given in
Table 1 and supplementary table S1. Fig. 2 displays the cell content in
M1BZP. It has a ‘U’ shape structure with two limbs which are benzyl and
mesitylene rings with a difference of 72◦ from the piperidine ring in the
base. The crystal structure of M1BZP revealed that the nitrogen atom of
R indices (all data)
R1 = 0.0617, wR2 = 0.1616
ꢀ 8.0(10)
Absolute structure parameter
Extinction coefficient
0.07(2)
Largest diff. peak and hole
0.179 and ꢀ 0.185 e.Åꢀ 3
Fig. 1. Thermal Ellipsoid View of M1BZP.
3

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
ring, second
π
-
π
: 2.95 Ǻ, centroid of piperidine… centroid of benzyl ring
and third π-π: 2.840 Ǻ, centroid of benzyl ring… centroid of mesityl
–
–
ring]. C H… N and C H… C intermolecular hydrogen bond in-
teractions along with C..H short interactions played a significant role in
stabilizing the molecular structure. These
π-π stacking interactions
created a perpendicular arrangement of piperidine moiety and benzyl
rings. One M1BZP molecule is connected to five other molecules through
–
–
weak C H… N, C H…
π and π-π interactions. The weak intermolecular
interactions and slip stacking arrangement [32] lead to the formation of
different types of packing structures like sheets, tubes, and layered
structures (Fig. 4). Nitrogen plays a major role in the formation of
different packing structures by acting as a bridge between the layers.
3.3. Hirshfeld surface analysis
The Hirshfeld surface denotes the 3D image of intermolecular in-
teractions that occur in the molecules. This study plays a valuable
graphical tool to understand the intermolecular interactions in depth.
Hirshfeld surface and fingerprint plots were generated for the title
compound. A three-dimensional dnorm surface is a useful tool for
analyzing and visualizing the intermolecular interactions. White color
indicates medium proximity of outside atoms and red and blue colors
indicate close or little proximity. Red spots on the Hirshfeld surface are
related to the hydrogen bonding interactions. As shown in Fig. 5(c), the
red region on the Hirshfeld surface is prominent above the hydrogen
Fig. 2. Unit cell packing arrangement viewed through crystallographic axis a*
the piperidine ring distorts the planarity of the structure by twisting C10
about 0.148 Å from the plane of the mesityl ring. The distortion in
planarity due to nitrogen atom is reflected from the dihedral angles ꢀ 2.1
◦
◦
(4) and 176.2(2) for C10-C1-C2-C7 and C10-N1-C11-C12 respec-
tively. Bond lengths of N1-C10 and C1-C10 are 1.472(4) and 1.512(4) Å
respectively. In M1BZP, the torsion angles of C14-C13-C16-C17 and
C15-N1-C10-C1 are 61.6(3) ◦ and ꢀ 60.2(3) ◦ respectively. It shows that
the benzyl and mesityl rings are in an acute position from the central
piperidine ring.
–
–
atom in the C H–N contacts and the H C..H contacts, respectively. The
red spots on the di (Fig. 5a) and de (Fig. 5b) surface indicate the exis-
tence of close contacts available inside and outside the surface. The
Crystal structure analysis of the compound revealed the presence of a
large number of non-covalent interactions such as inter and intra-
shape-index (Fig. 5d) of the HS can visualize π-π stacking interactions by
the presence of adjacent red and blue triangles. The curvedness (Fig. 5e)
surface indicates the electron density surface around the molecular in-
teractions. Moreover, the flat green region separated by blue edges in
–
molecular hydrogen bond interactions, C H… π, π… π stacking, and
inter short interactions [31] (Fig. 3). Weak intermolecular hydrogen
bonding interaction was observed in M1BZP between the hydrogen
atom (H10) of the mesityl ring (donor) and the nitrogen atom (N1) of the
neighbouring piperidine ring (acceptor). H-bonds are formed between
the curvedness surface is another characteristic of
interactions.
π-π stacking
The percentage contributions of intermolecular hydrogen bond in
the molecule are calculated using a 2D fingerprint plot from Hirshfeld
surface analysis. The intermolecular interaction pattern outlined as H… .
H / C… H is shown in Fig. 6. The H… .H contribution contact in the
Hirshfeld surface of the studied molecule is 80.7%. The presence of C… .
H / H… .C contribution in Hirshfeld surface is 19.3%. The most domi-
nant interaction in the title molecule is indicated by the symmetrical
narrow point spike with di + de ~ 2.2Ǻ corresponding to H… .H inter-
action as shown in Fig. 6, similarly, the shark characteristic wing of di +
–
–
π with an average length of 2.7 Å. The C H····π interactions are
C
H····
observed between the
π
-system of the benzene ring with the C16-H16
atoms of the neighbouring piperidine ring. The van der Waals repul-
sion shows that the nitrogen atom was sandwiched between mesitylene
and piperidine rings. M1BZP exhibited π-π stacking supramolecular in-
teractions in the crystal due to their aromatic moieties with a short
contact distance of < 3.2 Ǻ. There are three stacking interactions
[First : 3.1 Ǻ, the centroid of mesityl ring… .centroid of piperidine
π-π
π-π
Fig. 3. Molecular interactions viewed through crystallographic axis a*
4

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
Fig. 4. Different Packing arrangement of M1BZP.
Fig. 5. View of the three-dimensional Hirshfeld surface of M1BZP.
C-H (19.3 %)
H-H (80.7 %)
Fig. 6. The full two-dimensional fingerprint plots for the compound M1BZP.
de ~ 3.6 Ǻ corresponding to C… ..H / H… ..C are shown in Fig. 6.
(Eg) of the title molecule is ꢀ 5.7390 eV, which has a significant effect on
the stability and reactivity of the molecule [36]. The large bandgap of
the compound indicates high stability, less conjugation, and poor con-
ductivity. The interaction taking place within the molecule is respon-
sible for imparting bioactivity [37]. EHOMO and ELUMO values give details
of the certain charge exchange collaboration inside the studied mole-
cule. The HOMO energy determines the electron-donating ability.
However, the LUMO energy provides the ability of a molecule to accept
an electron [38]. The corresponding EHOMO and ELUMO values were
found to be ꢀ 5.6190 eV and 0.1200 eV respectively. The global reactive
parameters such as ionization energy (I), electron affinity (A), electro-
3.4. DFT Studies:
The optimized geometry and electronic parameters (bond lengths,
bond angles, EHOMO-ELUMO) of the compound were done using the
B3LYP/6–311++G(d,p) level of theory. The optimized geometry of
compound M1BZP is given in Fig. 7. The optimized structure results are
consistent with X-ray diffraction data. The geometrical parameters
(bond lengths and bond angles) of the structure are compared and
exhibited in the supplementary Table S2. FMO theory explicates the
structure, reactivity, electrical and optical properties of compound
[33,34]. The stabilized ground state energy of the system with the
minima point is found to be ꢀ 910.520 Hartree. The HOMO and LUMO
[35] structures are displayed in Fig. 8a. The HOMO-LUMO energy gap
negativity(
χ), hardness (
η
), softness (
σ), chemical potential (μ) and
electrophilicity index (
Table 2.
ω) of the molecule are calculated and recorded in
The molecular electrostatic potential (MEP) was defined in terms of
5

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
Fig. 7. Optimized Molecular structure of M1BZP.
used in drug design [39-41]. The optimized geometry at the B3LYP/
6–311++G(d,p) level of theory was used to map the molecular elec-
trostatic potential surface (MEPS) of the compound as shown in Fig. 8b.
It helps to investigate the interaction between molecules, predict reac-
tion sites, and molecular properties. Electron density is essential to un-
derstand the electrophilic or nucleophilic reactivity as well as non-
bonding interactions [42] at the MEP surface. Different colours repre-
sent different electrostatic potential values. Red and blue colours indi-
cate electron-rich and electron-poor regions respectively, and green
indicates zero electrostatic potential.
Mulliken charges were calculated at the B3LYP/6–311++G(d,p)
basis set are listed in Table 3. The nitrogen atom of the piperidine ring is
found to possess a high negative charge with a value of ꢀ 0.4177e when
compared with other atoms. This is mainly due to its participation in
–
C
H… N hydrogen bonding interactions. The carbon atoms C3, C5, C7,
C8, C12, C25, C26, C27, C28, C29, C32, C38, C39, C40, C41, C42 acquire
a negative charge while other carbon atoms of the molecule acquire a
positive charge. Among the carbon atoms, C4 possesses the highest
positive value and C8 has the highest negative value. The highest posi-
tive charge on C4 is due to the adjacent electronegative carbon atoms.
All the hydrogen atoms of the molecule are positively charged out of
which H21 (0.1397 e) has the highest charge.
3.5. Molecular docking studies
Fig. 8a. Calculated frontier molecular orbital profile.
According to molecular docking studies, a ligand molecule may
Table 2
The energy and related quantum chemical parameters values
of M1BZP.
Parameters
M1BZP
HOMO
ꢀ 5.6190
0.1200
LUMO
Band gap
ꢀ 5.7390
5.6190
Ionisation potential
Electron affinity
Chemical potential
Chemical hardness
Global softness
Electrophilic index
Absolute electronegativity
Q-max
ꢀ 0.1200
ꢀ 2.7495
2.8695
0.3485
10.8464
2.7495
0.9582
the total charge distribution of a molecule and it is a convenient tool
Fig. 8b. Graphical view of the molecular electrostatic potential (MEP) map.
6

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
protein than Remdesivir.
Table 3
Mulliken Charge analysis of M1BZP.
3.5.2. Interaction of Papin-like protease (PLpro) (4OVZ) with M1BZP
Atom
Charge
Atom
Charge
The docking studies of M1BZP and Remdesivir with the papin-like
C1
0.0162
0.1025
ꢀ 0.1711
0.1426
ꢀ 0.1710
0.1105
ꢀ 0.0878
ꢀ 0.3851
0.0631
ꢀ 0.3804
0.0640
ꢀ 0.3836
0.1201
0.1048
0.1195
0.1113
0.1235
0.1111
0.0987
0.1098
0.1397
0.0726
0.0949
ꢀ 0.4177
ꢀ 0.0316
ꢀ 0.1792
C27
C28
C29
H30
H31
C32
H33
H34
H35
H36
C37
C38
C39
C40
C41
C42
H43
H44
H45
H46
H47
H48
H49
H50
H51
H52
ꢀ 0.0566
ꢀ 0.1805
ꢀ 0.0222
0.1093
0.0998
ꢀ 0.2411
0.0977
0.0915
0.0921
0.0971
0.1228
ꢀ 0.1256
ꢀ 0.0839
ꢀ 0.0875
ꢀ 0.0849
ꢀ 0.1171
0.0795
0.0827
0.0821
0.0825
0.0765
0.0643
0.0848
0.0818
0.0944
0.0642
protease (4OVZ) [44] were carried out (Fig. 10). M1BZP has π-π stack-
C2
ing interactions with the Tyr269, Tyr265, Glu204, Glu162, and Glu165
amino acids with an average bond length of 4.30Ǻ. It also has hydrogen
bonding interactions with Tyr269, Arg167, Asn157, and Lys158 and
hydrophobic interactions with Pro249 and Try208. The binding energy
of papin-like protease with M1BZP is found to be ꢀ 9.7 kcal/mole. In the
case of standard drug, it has hydrophobic interactions with Tyr265,
Tyr269, Leu163, Pro224, Met209, and hydrogen bonding interactions
with the Asp165 amino acids. The binding energy of Remdesivir is found
to be ꢀ 9.4 kcal/mole. The above results revealed that M1BZP favours
Papin-like protease over Remdesivir.
C3
C4
C5
C6
C7
C8
H9
C10
H11
C12
H13
H14
H15
H16
H17
H18
H19
H20
H21
H22
H23
N24
C25
C26
3.5.3. Interaction of spike glycoprotein with ACE2 receptor (6ACD) with
M1BZP
For M1BZP, three types of interactions are observed with the spike
glycoprotein [45] (Fig. 11). It has hydrogen bonding interactions with
the amino acids Arg996, Gln939, Gln992, Arg100, and Gln936. It also
has hydrophobic interaction with Ala940, Leu944, Ala940 involving the
carbon atoms of the piperidine rings. Electrostatic interaction is
observed between the nitrogen atom of the piperidine ring and Arg996
with a binding energy of ꢀ 7.4 kcal/mole. On the other hand, Remdesivir
gives a binding affinity of ꢀ 6.0 kcal/mole on binding with spike
glycoprotein. It has hydrogen bonding interactions with Leu944,
Ala748, Arg747, Ala940, and one hydrophobic interaction with Thr988
amino acid. This result also has revealed that M1BZP showed good
binding with the spike glycoprotein than Remdesivir.
reduce or eliminate the SARS-CoV-2 by targeting different stages of the
virus life cycle in the host cell. When the compound was analyzed by in
silico computational docking, it was found to be successfully docked
against the inhibitor region of the main protease, RNA dependent RNA
polymerase, spike protein, and spike binding domain with ACE2 re-
ceptor of SARS-CoV-2 virus.
3.5.4. Interaction of the Main protease (6LU7) with M1BZP
Molecular docking of M1BZP and Remdesivir with SARS-CoV-2 spike
binding domain with Main protease [46] were analyzed and compared.
Binding free energy of ¡6.2 and ꢀ 5.4KJ/mol for M1BZP and Remdesivir
(Fig. 12) in the grid box were explored. These results suggest the high
affinity of M1BZP towards different amino acids Arg4, Lys137 with
hydrophobic interactions. It has electrostatic interactions with Glu288,
Arg4 amino acids. And hydrogen bonding interactions are observed
between M1BZP with Lys5. In Remdesivir, there is a hydrogen bonding
interaction with Phe291 and a hydrophobic interaction with Cys128. It
is observed that the SARS-CoV-2 spike binding domain with the Main
protease complex more favourably binds with M1BZP than Remdesivir.
3.5.1. Interaction of spike receptor protein (2AJF) with M1BZP
The molecular docking analysis of M1BZP and Remdesivir with
SARS-CoV-2 spike receptor protein [43] (Fig. 9) showed ¡8.2 and ꢀ 8.0
KJ/mol free energy respectively, suggesting a high affinity for the
binding pocket. It is observed that binding conformations of M1BZP are
found in the active binding sites. The title compound binds with Trp349,
Asp350, and His401 through hydrophobic interactions such as
π-π
stacking interactions. It has hydrogen bonding interactions with amino
acid residues such as Asp382, Ala348, and Asn394 with an average
distance of 2.15Ǻ. In the case of Remdesivir, hydrophobic interaction is
observed between His401 and Hydrogen bonding interaction with
Trp349. Thus, it is observed that M1BZP best binds with SARS Spike
M1BZP
Remdesivir
Fig. 9. Interaction of Spike receptor protein (2AJF) with M1BZP and Remdesivir.
7

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
M1BZP
Remdesivir
Fig. 10. Interaction of Papin-like protease (PLpro) (4OVZ) with M1BZP and Remdesivir.
M1BZP
Remdesivir
Fig. 11. Interaction of Spike glycoprotein with ACE2 receptor (6ACD) with M1BZP and Remdesivir.
M1BZP
Remdesivir
Fig. 12. Interaction of Main protease (6LU7) with M1BZP and Remdesivir.
3.5.5. Interaction of RNA dependent RNA polymerase (6 M71) with
M1BZP
binding pocket (Fig. 13). M1BZP binds with the binding pockets of
protein through hydrogen bonding interactions with Arg553, Arg555,
Thr556, Lys621, Cys622, Asn691, Thr556 amino acids, and hydrophobic
interactions with Cys622, Tyr445, Arg624. In Remdesivir hydrophobic
interactions with Arg553, Lys621, Tyr455, Asp760, and hydrogen
bonding interaction with Asp623 amino acid were found. In the case of
The docking analysis of M1BZP and Remdesivir with SARS-CoV-2
RNA-dependent RNA polymerase [47] were carried out and the results
revealed that free energy of M1BZP (-7.4KJ/mol) dominates Remdesivir
(-6.0KJ/mol) in the grid box, suggesting a high affinity towards the
8

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
M1BZP
Remdesivir
Fig. 13. Interaction of RNA dependent RNA polymerase (6M71) with M1BZP and Remdesivir.
RNA-dependent RNA polymerase, M1BZP binding is more favourable.
3.5.8. Interaction of SARS-CoV Main protease (6Y84) with M1BZP
The molecular docking studies of SARS-CoV Main protease [50] with
M1BZP and Remdesivir show binding affinity of ꢀ 6.5 kcal/mol and
ꢀ 5.0 kcal/mol respectively. In M1BZP the binding pockets are Gln110
and Ser158 through hydrogen bonding interactions and Val104, Ile106,
Cys160 through hydrophobic interactions. In Remdesivir, there is one
hydrophobic interaction with Val104 and one hydrophobic interaction
with Gln110. Thus, it is observed that the binding of M1BZP with SARS-
CoV Main protease is more favourable than Remdesivir (Fig. 16).
Based on the docking studies, M1BZP shows good orientations with
all the proteins of SARS-Cov and also shows good binding affinities. This
may be due to the flexible nature of M1BZP having U shaped structure.
3.5.6. Interaction of spike binding domain with ACE2 receptor (6MOJ)
with M1BZP
The docking analysis of the M1BZP and Remdesivir with SARS-CoV-2
spike binding domain with ACE2 receptor [48] (Fig. 14) results in ¡4.5
and ꢀ 4.4 KJ/mol free energy respectively in the grid box, suggesting a
high affinity for the binding pocket. All the binding modes of the com-
pound are in the active binding pocket. The M1BZP binds with the
amino acid residues Val151, Ala154, Leu121, Met158, His159, Ala154,
Leu188 through hydrophobic interactions and Remdesivir binds with
Val130, His159, Glu125 amino acids through hydrogen bonding in-
teractions. Thus, it is observed that M1BZP favours SARS-CoV-2 spike
binding domain with the ACE2 receptor complex over Remdesivir.
3.6. ADME and Toxicity Prediction:
3.5.7. Interaction of spike glycol protein (6VSB) with M1BZP
Many drugs fail in the drug development process due to their poor
pharmacokinetics and toxicity problems. Drawbacks arising during drug
development could be addressed at the early stage in the pipeline of this
process [51]. To analyse this issue of new chemical compounds, in silico
ADMET methods are the first step in this pipeline process. These
methods avoid wasting time on a lead compound that would be toxic or
metabolized by the body into an inactive form and unable to cross
membranes. These ADMET parameters disclose the behaviour of the
chemical compounds in a living organism. Understanding physico-
chemical properties are necessary for designing new pharmacological
compounds. A drug-likeness profile can be evaluated through the pa-
rameters of the molecule such as molecular weight, TPSA, number of
The molecular docking analysis M1BZP and Remdesivir with SARS-
CoV-2 spike glycol protein [49] revealed ¡3.9 and ꢀ 3.6KJ/mol free
energy respectively (Fig. 15), suggesting a high affinity for the binding
pocket. It is observed that binding conformations of the M1BZP are in
the active binding sites. M1BZP compound binds with Val100, Ala766,
Leu763, and Leu101 through hydrophobic interactions. It also has
hydrogen bonding interaction with Thr100, Gln100, Phe759, Gln762
with an average distance of 2.5Ǻ. Remdesivir has Hydrogen bonding
interactions with Gln100, Thr100, Gln101 and hydrophobic interactions
with Ala766, Leu763, Val100 amino acids. Thus, it is observed that
M1BZP binds best with SARS Spike protein than Remdesivir.
M1BZP
Remdesivir
Fig. 14. Interaction of spike binding domain with ACE2 receptor (6MOJ) with M1BZP and Remdesivir.
9

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
M1BZP
Remdesivir
Fig. 15. Interaction of Spike glycol protein (6VSB) with M1BZP and Remdesivir.
M1BZP
Remdesivir
Fig. 16. Interaction of SARS-CoV Main protease (6Y84) with M1BZP and Remdesivir.
heavy atoms, HBA, HBD, rotatable bonds, and molar refractivity. The
physicochemical parameters of M1BZP were calculated using Osiris data
warrior and depicted in Table 4. Bioavailability radar shows that all
parameters such as XLOGP3 = 4.25 (-0.7 to + 5.0), Molecular weight =
307.47 g/mol (150 to 500 g/mol), Solubility (Log S) = -5.36 (log S not
higher than 6), Flexibility (FLEX) = 4 (not more than 9 rotatable bonds)
lie within the acceptable range except Saturation (INSATU) = 0.45
(not<0.25) [29,52]. The M1BZP shows drug-likeness from all methods
such as Lipinski, Ghose, Veber, Egan, and Muegge. The results of these
predictions showed that the compound obeyed all the five rules along
with the standard without any violation of the bioactivity score of 0.55.
Further, the synthetic accessibility of the compound was assessed to
quantify the complexity of the molecular structure. The results showed
that the compound does not have a complex synthetic route based on
their score in the range of 2.52.
Table 4
Physicochemical parameters generated using Osiris datawarrior.
Property Name
Property Value
Molecular Weight
Clog P
307.47 g/mol
5.1584
ꢀ 4.413
0
Clog S
The mean predicted lipophilicity values were assessed to decide the
non-aqueous solubility of the compound and were calculated by
considering the consensus log Po/w. According to this, if a molecule is
more soluble, then its consensus log Po/w values will be more negative.
Results showed that the compound is not soluble in a non-aqueous
medium and to estimate the aqueous solubility log S scale was used:
According to the log S scale the compound is moderately soluble (-5.3).
(if log S < ꢀ 10 - poorly soluble, < ꢀ 6 - moderately soluble, < ꢀ 4 -
soluble, < ꢀ 2 - very soluble, and < 0 highly soluble) [53-56].
Hydrogen Bond Donor Count
Hydrogen Bond Acceptor Count
Rotatable Bond Count
Total Surface Area
Relative PSA
1
4
261.66
0.01356
3.24
PSA
Shape Index
0.6521
0.4815
0.6920
0
Molecular Flexibility
Molecular Complexity
Stereo Centres
Druglikness
4.2521
10

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
The pharmacokinetic parameters like absorption, skin permeation,
distribution, and metabolism/biotransformation/excretion were pre-
dicted. For gastrointestinal absorption and passive brain permeation
Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is
known to predict an accurate result. According to this predictive model
(Fig. 17) molecule falls in the yellow region which indicates passive
brain permeation. It is evident from this predictive result that the
compound had high GI absorption and high BBB permeant as tabulated
in Table 5. The compound being blood–brain permeant there may be a
possibility of causing harmful toxicants in the brain and bloodstream
when metabolized. The skin permeability model can predict and identify
potential drugs for oral and transdermal administration. As per the
model, if a molecule has more negative log Kp value it is said to be less
skin permeant. Based on this the compound was found to be the least
skin permeant.
Table 5
Pharmacokinetics of M1BZP evaluated using SwissADME tool.
Parameters
Pharmacokinetic
GI Absorption
High
BBB Permeant
Yes
P-gp Substrate
No
CYP1A2 Inhibitor
CYP2C19 Inhibitor
CYP2C9 Inhibitor
CYP2D6 Inhibitor
CYP3A4 Inhibitor
Log KP (Skin permeation)
No
No
No
Yes
No
ꢀ 4.24 cm/s
Table 6
Toxicology of M1BZP evaluated using SwissADME tool.
The permeability glycoprotein (P-gp) is an important protein that
plays a significant role in drug absorption and disposition. Hence, the
compound was evaluated to determine whether the compound can act as
a substrate or an inhibitor of P-gp and results revealed that the com-
pound is found to be non-substrates of P-gp. Interaction of molecules
with cytochrome P450 (CYP) enzymes is essential because these iso-
enzymes are involved in drug elimination through metabolic trans-
formation. Inhibition of these isoenzymes may result in unwanted
adverse side-effects by lowering the solubility and the accumulation of
the drug or its metabolites. Prediction reveals that the compound act as a
non-inhibitor for CYP2C9 whereas CYP1A2 acts as inhibitors of CYP2D6.
Compound M1BZP is predicted to be CYP3A4 non-substrate and for the
isoenzyme, CYP2C19 were non-inhibitors.
Parameters
Toxicity
AMES Toxicity
Less toxic
Max. Tolerated Dose (human)
HERG 1 Inhibitor
0.383
No
HERG 2 Inhibitor
Yes
Oral Rate Acute Toxicity (LDSO)
Oral Rate Chronic Toxicity (LOAEL)
Hepatotoxicity
2.783 mol/kg
1.233(log mg/kg_bw/day)
Yes
Skin Sensitization
No
T. Pyriformis Toxicity
Minnow Toxicity
1.727 log mg/L
ꢀ 0.109 log mM
3.7. Conclusion
Toxicity prediction by computational technique is one of the new
techniques in the drug development process, the modern era which
consumes less time and low cost. Toxicity prediction of chemical entities
is important to predict the amount of tolerability of the chemical entities
before entering into in-vivo studies. The maximum tolerated dose of
M1BZP is 0.383(log mg/kg_bw/day). The compound M1BZP shows
chronic toxicity is 1.233(log mg/kg_bw/day). The Predicted LD50
values ranged from 2.77 to 2.783 mol/kg. The liver plays a critical role
in energy exchanges and the biotransformation of xenobiotics and drugs.
Liver suffering from damage always disrupts normal metabolism and
could even lead to liver failure. The hepatotoxicity descriptor predicted
that a molecule could present hepatotoxicity. The toxicity was predicted
using the pkCSM online tool [57] and its results indicate that the com-
pound M1BZP is less toxic (Table 6). Thus, these in silico properties are
appreciable. Therefore, further studies of in vitro and clinical studies
dealing with SARS-CoV-2 would be carried out.
The structures of potential targets of COVID-19 were chosen based
upon the literature of the coronavirus life cycle. In the aim of discov-
ering a new potent drug against COVID-19, M1BZP was applied against
eight proteins and found to be higher activity than expected. Molecular
docking was performed to predict the binding modes between the tar-
gets and M1BZP. The docking results produced by autodock vina models
reveal the important sites where steric, electrostatic, and hydrophobic
interactions might significantly influencing the activity of the mole-
cules. X-ray structural analysis of M1BZP revealed several intermolec-
–
ular interactions (hydrogen bond, short interactions, C H…
π and π… π)
which greatly contributed to the ligand–protein binding process. These
interactions are well quantified by Hirshfeld surface analysis. The
compound was predicted to display low toxicity levels and showed drug-
likeness according to the Lipinski and Veber rules. Thus, these in silico
properties are appreciable. The compound shows good binding with the
Fig. 17. (a) The BOILED-Egg model and (b) Bioavailability radar of M1BZP.
11

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
[23] M.W. Schmidt, K.K. Baldridge, J.A. Boatz, S.T. Elbert, M.S. Gordon, J.H. Jensen,
S. Koseki, N. Matsunaga, K.A. Nguyen, S. Su, T.L. Windus, M. Dupuis, J.
A. Montgomery, General atomic and molecular electronic structure system, Journal
of Computational Chemistry 14 (1993) 1347–1363.
papin like protease. Based on the comparison with Remdesivir, the
M1BZP molecule showed good interaction with target proteins, which
may be a competitive drug alternative for Remdesivir.
[24] R.M. Hanson, ‘Jmol SMILES and Jmol SMARTS: specifications and applications’,
Journal of, Cheminformatics 8 (2016) 50.
Declaration of Competing Interest
[25] J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Towards quantitative analysis of
intermolecular interactions with Hirshfeld surfaces, Chem. Commun. 37 (2007)
3814–3816.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
[26] G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.
J. Olson, AutoDock4 and AutoDockTools4: automated docking with selective
receptor flexibility, J. Comput. Chem. 30 (2009) 2785–2791.
[27] O. Trott, A.J. Olson, Auto Dock Vina: improving the speed and accuracy of docking
with a new scoring function, efficient optimization, and multithreading, J. Comput.
Chem. 31 (2010) 455–461.
Appendix A. Supplementary material
[28] R. Herowatia, G.P. Widodo, Molecular docking studies of chemical constituents of
Tinosporacordifolia on glycogen phosphorylase, Procedia Chem. 13 (2014) 63–68.
[29] A. Daina, O. Michielin, V. Zoete, SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules, Scientific reports 7 (2017) 42717.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104967.
[30] D.E. Pires, T.L. Blundell, D.B. Ascher, pkCSM: Predicting Small-Molecule
Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures, Journal of
medicinal chemistry 58 (2015) 4066–4072.
References
[1] Z. Song, X.u. Yanfeng, L. Bao, L. Zhang, Y.u. Pin, Q.u. Yajin, H.a. Zhu, W. Zhao,
Y. Han, C. Qin, From SARS to MERS, thrusting coronaviruses into the spotlight,
Viruses 11 (2019) 59.
[31] G.A. Jeffrey, W. Saenger, Hydrogen Bonding in Biological Structures, Springer,
London, 1994.
[32] Z.F. Yao, J.Y. Wang, J. Pei, Control of p–p stacking via crystal engineering in
organic conjugated small molecule crystals, Cryst. Growth Des. 18 (2018) 7–15.
[33] M.O. Almeida, D.A. Barros, S.C. Araujo, S.H. Faria, V.G. Maltarollo, K.M. Honorio,
Study on molecular structure, spectroscopic properties (FTIR and UV–Vis), NBO,
QTAIM, HOMO-LUMO energies and docking studies of 5-fluorouracil, a substance
used to treat cancer, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 5 (2017)
169–176.
[2] B.T. Thompson, R.C. Chambers, K.D. Liu, Acute respiratory distress syndrome,
N. Engl. J. Med. 377 (2017) 562–572.
[3] Simon J Anthony, Christine K Johnson, Denise J Greig, Sarah Kramer, Xiaoyu Che,
Heather Wells, Allison L Hicks, Damien O Joly, Nathan D Wolfe, Peter Daszak,
William Karesh, W I Lipkin, Stephen S Morse, PREDICT Consortium; Jonna A K
Mazet, Tracey Goldstein, Global patterns in coronavirus diversity, Virus Evol, 2017
3 (1) vex012.
[34] I. Rajaei, S.N. Mirsattari, Spectroscopic characteristic (FT-IR, 1H, 13C NMR and
UV–Vis) and theoretical calculations (MEP, DOS, HOMO-LUMO, PES, NBO analysis
and keto-enol tautomerism) of new tetradentate N, N′-bis (4-hydroxysalicylidene)-
1, 4-phenylenediamine ligand as a chelating agent for the synthesis of dinuclear Co
(II), Ni (II), Cu (II) and Zn (II) complexes, J. Mol. Struct. 1163 (2018) 236–251.
[35] A. Soltani, F. Ghari, A.D. Khalaji, E. Tazikeh Lemeski, K. Fejfarova, M. Dusek,
M. Shikhi, Crystal structure, spectroscopic and theoretical studies on two Schiff
base compounds of 2,6-dichlorobenzylidene-2,4-dichloroaniline and 2,4-
dichlorobenzylidene-2,4-dichloroaniline, Spectrochim. Acta A. Mol. Biomol.
Spectrosc. 139 (2015) 271–278.
[4] A.R. Fehr, S. Perlman, Coronaviruses: an overview of their replication and
pathogenesis, Methods Mol. Biol. 1282 (2015) 1–23.
[5] A.A. Elfiky, Anti-HCV, nucleotide inhibitors, repurposing against COVID-19, Life
Sciences 248 (2020), 117477.
[6] M. Romano, A. Ruggiero, F. Squeglia, G. Maga, R. Berisio, A Structural View of
SARS-CoV-2 RNA Replication Machinery, RNA Synthesis, Proofreading, and Final
Capping. Cells 9 (2020) 1267.
[7] R.J. Hulswit, C.A. de Haan, B.J. Bosch, Coronavirus Spike Protein and Tropism
Changes, Adv. Virus Res. 96 (2016) 29–57.
[8] J. Wang, Fast identification of possible drug treatment of coronavirus disease-19
(COVID-19) through computational drug repurposing study, Journal of Chemical
Information and Modeling 60 (2020) 3277–3286.
[36] M.H. Helal, S.A. El-Awdan, M.A. Salem, T.A. Abd-Elaziz, Y.A. Moahamed, A.A. El-
Sherif, G.A. Mohamed, Synthesis, biological evaluation and molecular modeling of
novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic
agents, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 25 (2015) 764–773.
[37] H. Singh, ADFT approach for theoretical and experimental study of structure,
electronic, Hirshfeld surface and spectroscopic properties of 12-(4bromophenyl)-2-
(prop-2-ynyloxy)-9,10-dihydro-8H-benzo[a]xanthen11(12H)-on single crystal,
Chemical Physics 524 (2019) 1–13.
[9] V. Vijayan, P. Pant, N. Vikram, P. Kaur, T.P. Singh, S. Sharma, P. Sharma,
Identification of promising drug candidates against NSP16 of SARS-CoV-2 through
computational drug repurposing study, Journal of Biomolecular Structure and
Dynamics (2020) 1–15.
ˇ
[10] A. Fischer, M. Sellner, S. Neranjan, M. Smiesko, M.A. Lill, Potential Inhibitors for
Novel Coronavirus Protease Identified by Virtual Screening of 606 Million
Compounds, International Journal of Molecular Sciences 21 (2020) 3626.
[11] Pei Liu, Hongbo Liu, Qi Sun, Hao Liang, Chunmei Li, Xiaobing Deng, Ying Liu,
Luhua Lai, Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-
substituted isatin compounds, European Journal of Medicinal chemistry, 2020
(206) 112702.
[38] S. Sakthivel, T. Alagesan, S. Muthu, C.S. Abraham, E. Geetha, Quantum
mechanical, spectroscopic study (FT-IR and FT - Raman), NBO analysis, HOMO-
LUMO, first order hyperpolarizability, and docking studies of a non-steroidal anti-
inflammatory compound, Journal of Molecular Structure 1156 (2018) 645–656.
[39] G. Pepe, D. Siri, J.-P. Reboul, The Molecular Electrostatic Potential, and Drug
Design, Journal of Molecular Structure 256 (1992) 175–185.
[12] S. Chidambaram, M.A. El-Sheikh, A.H. Alfarhan, S. Radhakrishnan, I. Akbar,
Synthesis of novel coumarin analogues: Investigation of molecular docking
interaction of SARS-CoV-2 proteins with natural and synthetic coumarin analogues
and their pharmacokinetics studies, Saudi Journal of Biological Sciences 28 (2021)
1100–1108.
[40] C.F. Matta, Modeling biophysical and biological properties from the characteristics
of the molecular electron density, electron localization and delocalization matrices,
and the electrostatic potential, J. Comput. Chem. 35 (2014) 1165–1198.
[41] S.R. Sebastian, M.I. Attia, M.S. Almutairi, A.A. El-Emam, C.Y. Panicker, C. Van
Alsenoy, FT-IR, FT-Raman, molecular structure, first order hyperpolarizability,
HOMO and LUMO analysis, MEP and NBO analysis of 3-(adamantan-1-yl)-4-(prop-
2en-1-yl)-1H-1, 2, 4-triazole-5 (4H)-thione, a potential bioactive agent,
Spectrochim. Acta A Mol. Biomol. Spectrosc. 11 (2014) 295–304.
[13] F. Ooms, Molecular modeling and computer-aided drug design. Examples of their
applications in medicinal chemistry, Curr. Med. Chem. 7 (2000) 141–158.
[14] S.V. Jain, M. Ghate, K.S. Bhadoriya, S.B. Bari, A. Chaudhari, J.S. Borse, 2D, 3D-
QSAR and docking studies of 1, 2, 3-thiadiazole thioacetanilides analogues as
potent HIV-1 non-nucleoside reverse transcriptase inhibitors, Organic Med. Chem.
Lett. 2 2012 (1) 22.
[42] V.R. Hartwar, M. Sist, M.R.V. Jorgensen, A.H. Mamakhel, X. Wang, C.
M. Hoffmann, K. Sugimoto, J. Overgaard, B.B. Iversen, Quantitative analysis of
intermolecular interactions in orthorhombic rubrene, IUCrJ 2 (2015) 563–574.
[43] F. Li, W. Li, M. Farzan, S.C. Harrison, Structure of SARS coronavirus spike receptor-
binding domain complexed with the receptor, Science 309 (2005) 1864–1868.
[44] Y.M. Baez-Santos, S.J. Barraza, M.W. Wilson, M.P. Agius, A.M. Mielech, N.
M. Davis, S.C. Baker, S.D. Larsen, A.D. Mesecar, X-ray Structural and Biological
Evaluation of a Series of Potent and Highly Selective Inhibitors of Human
Coronavirus Papain-like Proteases, J Med Chem 57 (2014) 2393–2412.
[45] W. Song, M. Gui, X. Wang, Y. Xiang, Cryo-EM structure of the SARS coronavirus
spike glycoprotein in complex with its host cell receptor ACE2, PLoS Pathog 14
(2018) e1007236 e1007236.
[15] J. Zhang, Y. Shan, X. Pan, C. Wang, W. Xu, L. He, Molecular docking, 3D-QSAR
Studies, and in silico ADME prediction of p-aminosalicylic acid derivatives as
neuraminidase inhibitors, Chem. Biol. Drug Des. 78 (2011) 709–717.
[16] APEX3 “Program For Data Collection On Area Detectors” BRUKER AXS Inc., 5465
East Cheryl Parkway, Madison, USA WI 53711–5373.
[17] SADABS, G.M. Sheldrick, “Program For Absorption Correction of Area Detector
Frames”, BRUKER AXS Inc., 5465 East Cheryl Parkway, Madison, WI 53711–5373
USA.
[18] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Cryst. A64 (2008)
112–122.
[46] Z. Jin, X. Du, Y. Xu, Y. Deng, M. Liu, Y. Zhao, B. Zhang, X. Li, L. Zhang, C. Peng,
Y. Duan, J. Yu, L. Wang, K. Yang, F. Liu, R. Jiang, X. Yang, T. You, X. Liu, X. Yang,
F. Bai, H. Liu, X. Liu, L.W. Guddat, W. Xu, G. Xiao, C. Qin, Z. Shi, H. Jiang, Z. Rao,
H. Yang, Structure of Mprofrom SARS-CoV-2 and discovery of its inhibitors, Nature
582 (2020) 289–293.
[19] G.M. Sheldrick, SHELXT –Integrated space-group and crystal-structure, Acta Cryst.
A71 (2015) 3–8.
[20] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Cryst. C71 (2015)
3–8.
[21] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2
< /i>; a complete structure solution, refinement, and analysis program, J. Appl.
Cryst. 42 (2009) 339–341.
[47] Y. Gao, L. Yan, Y. Huang, F. Liu, Y. Zhao, L. Cao, T. Wang, Q. Sun, Z. Ming,
L. Zhang, J. Ge, L. Zheng, Y. Zhang, H. Wang, Y. Zhu, C. Zhu, T. Hu, T. Hua,
B. Zhang, X. Yang, J. Li, H. Yang, Z. Liu, W. Xu, L.W. Guddat, Q. Wang, Z. Lou,
Z. Rao, Structure of the RNA-dependent RNA polymerase from COVID-19 virus,
Science 368 (2020) 779–782.
[22] A.W. Van der Made, R.H. Van der Made, A convenient procedure for
bromomethylation of aromatic compounds: selective mono-, bis-, or
trisbromomethylation, J. Org. Chem. 58 (1993) 1262–1263.
12

R. Nandini Asha et al.
Bioorganic Chemistry 112 (2021) 104967
[48] K. Mohan, G. Ueda, A.R. Kim, K.M. Jude, J.A. Fallas, Y. Guo, M. Hafer, Y. Miao, R.
A. Saxton, J. Piehler, V.G. Sankaran, D. Baker, K.C. Garcia, Topological control of
cytokine receptor signaling induces differential effects in hematopoiesis, Science
364 (2019) 6442.
[52] A. Daina, O. Michielin, V. Zoete, iLOGP: A Simple, Robust, and Efficient
Description of n-Octanol/Water Partition Coefficient for Drug Design Using the
GB/SA Approach, J. Chem. Inf. Model. 54 (2014) 3284–3301.
[53] B. Debnath, S. Ganguly, Synthesis, biological evaluation, in silico docking, and
virtual ADME studies of 2-[2-Oxo-3-(arylimino) indolin-1-yl]-N-arylacetamides as
potent anti-breast cancer agents, Monatshefte für Chemie-Chemical Monthly 147
(2016) 565–574.
[49] D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.L. Hsieh, O. Abiona, B.
S. Graham, J.S. McLellan, Cryo-EM structure of the 2019-nCoV spike in the
prefusion conformation, Science 367 (2020) 1260–1263.
[50] C.D. Owen, P. Lukacik, C.M. Strain-Damerell, A. Douangamath, A.J. Powell,
D. Fearon, J. Brandao-Neto, A.D. Crawshaw, D. Aragao, M. Williams, R. Flaig, D.
R. Hall, K.E. McAuley, M. Mazzorana, D.I. Stuart, F. von Delft, M.A. Walsh, SARS-
CoV-2 main protease with unliganded active site (2019-nCoV, coronavirus disease
COVID-19) (2019) 2020.
[54] C.A. Lipinski, Drug-like properties and the causes of poor solubility and poor
permeability, J. Pharmacol. Toxicol. Methods 44 (2000) 235–249.
[55] C.A. Lipinski, Lead-and drug-like compounds: the rule-of-five revolution, Drug
Discov. Today: Technol. 1 2004 (4) 337–341.
[56] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and
computational approaches to estimate solubility and permeability in drug
discovery and development settings, Adv. Drug Deliv. Rev. 23 (1997) 3–25.
[57] A. Daina, O. Michielin, V. Zoete, SwissTargetPrediction: updated data and new
features for efficient prediction of protein targets of small molecules, Nucleic Acids
Res. 47 (2019) W357.
[51] C. Cook, S. McDonald, A. Karim, Importance of pharmacokinetic and
physicochemical data in the discovery and development of novel antiarrhythmic
drugs, Xenobiotica 23 (1993) 1299–1309.
13