Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO, NLO, NBO analysis and molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one, a potential precursor to bioactive agents

Article abstract of DOI:10.1016/j.molstruc.2016.07.044

The FT-IR and FT-Raman spectra of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one were recorded and analyzed experimentally and theoretically. The observed experimental and theoretical wavenumbers were assigned using potential energy distribution. The NLO properties were evaluated by the determination of first and second hyperpolarizabilities of the title compound. From the frontier molecular orbital study, the HOMO centers over the entire molecule except the methyl groups, while the LUMO is over the entire molecule except the CH₂ group with the dioxole ring and one of the methyl groups. From the MEP plot, it is evident that the negative region covers the carbonyl and [Formula presented] groups and the positive region is over CH₂ groups. The Fukui functions are also reported. The calculated geometrical parameters are in agreement with the XRD results. From the molecular docking study, the docked ligand title compound forms a stable complex with the androgen receptor and gives a binding affinity value of??8.1?kcal/mol and the results suggest that the compound might exhibit inhibitory activity against androgen receptor.

Full text of DOI:10.1016/j.molstruc.2016.07.044

Accepted Manuscript
Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO, NLO, NBO analysis
and molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-
one, a potential precursor to bioactive agents
Reem I. Al-Wabli, K.S. Resmi, Y. Sheena Mary, C. Yohannan Panicker, Mohamed A.
Attia, Ali A. El-Emam, C. Van Alsenoy
PII:
S0022-2860(16)30725-6
10.1016/j.molstruc.2016.07.044
MOLSTR 22747
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 6 March 2016
Accepted Date: 12 July 2016
Please cite this article as: R.I. Al-Wabli, K.S. Resmi, Y. Sheena Mary, C. Yohannan Panicker, M.A.
Attia, A.A. El-Emam, C. Van Alsenoy, Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO,
NLO, NBO analysis and molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-
en-3-one, a potential precursor to bioactive agents, Journal of Molecular Structure (2016), doi: 10.1016/
j.molstruc.2016.07.044.
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Graphical abstract
Title of the paper: Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO,
NLO, NBO analysis and molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-
dimethylpent-1-en-3-one, a potential precursor to bioactive agents

ACCEPTED MANUSCRIPT
Vibrational spectroscopic studies, Fukui functions, HOMO-LUMO, NLO, NBO analysis and
molecular docking study of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one, a
potential precursor to bioactive agents
a
b
c
c*
Reem I. Al-Wabli , K.S.Resmi , Sheena Mary Y , C.Yohannan Panicker , Mohamed A.
a,d
a
e
Attia , Ali A. El-Emam , C.Van Alsenoy
a
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451,Saudi Arabia
Department of Physics, TKM College of Arts and Science, Kollam, Kerala, India
c
Department of Physics, Fatima Mata National College, Kollam, Kerala, India
d
Pharmaceutical and Drug Industries Research Division, Department of Medicinal and
Pharmaceutical Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
e
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp,
Belgium
*
author for correspondence:email:cyphyp@rediffmail.com
ABSTRACT
The FT-IR and FT-Raman spectra of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-
one were recorded and analyzed experimentally and theoretically. The observed experimental
and theoretical wavenumbers were assigned using potential energy distribution. The NLO
properties were evaluated by the determination of first and second hyperpolarizabilities of the
title compound. From the frontier molecular orbital study, the HOMO centers over the entire
molecule except the methyl groups, while the LUMO is over the entire molecule except the
CH group with the dioxole ring and one of the methyl groups. From the MEP plot, it is
2
evident that the negative region covers the carbonyl and C=C groups and the positive region
is over CH groups. The Fukui functions are also reported. The calculated geometrical
2
parameters are in agreement with the XRD results. From the molecular docking study, the
docked ligand title compound forms a stable complex with the androgen receptor and gives a
binding affinity value of -8.1 kcal/mol and the results suggest that the compound might
exhibit inhibitory activity against androgen receptor.
Keywords: DFT; benzodioxole; FT-IR; FT-Raman; Molecular docking.
1
.
Introduction
,3-Benzodioxole moiety constitutes an essential structure motif in several naturally-
1
occurring [1-5] bioactive compounds. In addition, a considerable number of biomolecules
having 1,3-bezodioxole moiety display multifarious biological activities including
anticonvulsant [6-8], anti-depressant [9], anticancer [10,11], immunomodulatory [12] and
1

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antiprotozoal [13] activities. The title compound, (E)-1-(1,3-benzodioxol-5-yl)-4,4-
dimethylpent-1-en-3-one, is the precursor of the anticonvulsant orphan drug, stiripentol which
was clinically approved as anticonvulsant drug [14]. The molecular conformations of indan-
like benzene fused ring molecules including 1,3-benzodioxole derivatives have been
exclusively studied due to their interesting conformational properties [15-21]. Fun et al. [22]
reported the single crystal XRD study of the title compound. In the present study, the IR and
Raman spectra of the title compound are reported both experimentally and theoretically. In
addition, the NBO analysis, molecular electrostatic potential and nonlinear optical properties
are reported. The molecular docking studies are also reported due to the diverse biological
activities of 1,3-benzodioxole derivatives.
2
.
Experimental details
The title compound was prepared via condensation of equimolar amounts of piperonal
o
and pinacolone in aqueous methanolic potassium hydroxide at 70 C for five hours [8]. The
FT-IR spectrum (Fig. 1) was recorded using KBr pellets on a DR/Jasco FT-IR 6300
-1
spectrometer with a spectral resolution of 2 cm . The FT-Raman spectrum (Fig. 2) was
obtained on a Bruker RFS 100/s, Germany, and for excitation of the spectrum, the emission of
Nd:YAG laser was used, excitation wavelength was 1064 nm, maximal power was 150 mW
and measurement was carried out on solid sample.
3
.
Computational details
All calculations have been performed with the Gaussian09 program package using the
density functional theoretical method (DFT) with Becke-3-Lee-Yang-Parr (B3LYP)
combined with the standard basis set SDD (6D, 10F) [23] and since the DFT method tends to
overestimate the fundamental modes, a scaling factor of 0.9613 has to be used for obtaining a
considerable better agreement with the experimental data [24, 25]. The Stuttgart/Dresden
effective core potential basis set (SDD) [26] was chosen particularly because of its advantage
of doing faster calculations with relatively better accuracy and structures [27]. The parameters
corresponding to the optimized geometry (Fig. 3) of the title compound with the experimental
XRD data [22] are given Table S1 (supporting material). The assignments of the calculated
wavenumbers are aided by the Gaussview program [28] and potential energy distribution
analysis [29].
4
4
.
Results and discussion
.1
Geometrical parameters
For the title compound, the carbon-carbon bond lengths (DFT/XRD) in the phenyl ring
lies in the range 1.3891-1.4301/1.3668-1.4125 Å and the bond lengths are somewhere in
2

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between the normal values for a single (1.54 Å) and a double (1.33 Å) bond [30]. The bond
length (DFT/XRD) C -C is longer (1.4301/1.4125 Å) due to the presence of adjacent C=C
9
10
group. The C-O bond lengths (DFT/XRD) lie in the range 1.4058-1.4803/1.3685-1.4378 Å
which are in agreement with literature [31]. For the title compound, the bond lengths
(
DFT/XRD) C -C = 1.5450/1.5262, C -C = 1.5570/1.5363, C -C = 1.5570/1.5363,
14 15 14 28 14 16
C -C = 1.5482/1.5298 Å and these high values are attributed to the presence of the adjacent
1
3
14
methyl groups [31]. For the title compound, the C=O and C=C bond lengths (DFT/XRD) are
.2596/1.2214 and 1.3611/1.3465 Å, respectively, which are in agreement with reported
values [31, 32]. At C and C , the bond angles (DFT/XRD) are C -C -C = 121.6/121.9˚, C -
1
6
8
5
6
8
5
C -O = 128.0/128.2˚, C -C -O = 110.3/109.8˚, C -C -C = 122.4/122.4˚, C -C -O =
6
1
8
6
1
6
8
9
6
8
2
1
10.0/109.8˚ and C -C -O = 127.6/127.7˚ and this asymmetry in angles are due to the
9 8 2
hydrogen bonding in the molecule as reported in literature [22]. At C and C positions, the
1
0
13
bond angles (DFT/XRD) are C -C -C = 119.4/119.5˚, C -C -C = 118.1/119.0˚, C -C -C
11
4
10
9
4
10
11
9
10
=
122.4/121.4˚, C -C -C = 118.1/117.4˚, C -C -O = 121.1/121.6˚ and C -C -O =
14 13 12 14 13 3 12 13 3
1
20.8/120.9˚, and the asymmetry in the angles are due to the presence of adjacent groups. The
phenyl and 1,3-dioxole rings are planar as is evident from the torsion angles, C -C -O -C , C -
5
6
1
7
5
C -C -O , C -C -O -C and C -C -C -O (Table S1).
6
8
2
9
8
2
7
9
8
6
1
4
.2
IR and Raman spectra
The observed IR, Raman bands, calculated (scaled wavenumbers) and assignments are
given in Table 1. The CH stretching modes of the phenyl ring are theoretically assigned at
-1
3
126, 3123 and 3089 cm for the title compound [33] and only one band is observed in the
-1
Raman spectrum at 3124 cm . For tri-substituted phenyl ring the ring stretching modes are
-1
-1
expected in the region 1640-1250 cm [33] and these modes are assigned at 1605, 1585 cm
-1
in the IR spectrum, 1595, 1419 cm in the Raman spectrum and theoretically at 1599, 1581,
-1
1
463, 1425, 1359 cm . In asymmetric tri-substituted benzenes, the wavenumber interval of
-1
the ring breathing mode is expected at 500-600 cm when all the three substituents are light
33, 34]. When all the three substituents are heavy, the ring breathing mode wavenumber
[
-1
appears above 1100 cm and in the case of mixed substituent the wavenumber is expected to
-1
appear between 600 and 750 cm . For the title compound, the ring breathing mode of the
-1
-1
phenyl ring is theoretically assigned at 769 cm and bands are observed at 764 cm in the IR
-1
spectrum and at 766 cm in the Raman spectra, respectively. The ring breathing mode of a tri-
-1
substituted phenyl ring is theoretically reported at 796 cm by Panicker et al. [18] and at 733
-1
(
IR), 738 cm by Mary et al. [35]. The in-plane and out-of-plane CH deformation modes of
-1
the phenyl ring are expected above and below 1000 cm [33]. In the present case, the bands at
3

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-1
1
258, 1120 (IR), 1256 (Raman), 1254, 1180, 1117 cm (DFT) and 882, 830 (IR), 951, 828
-1
(
Raman), 949, 880, 824 cm (DFT) are assigned as the CH in-plane and out-of-plane
deformations of the phenyl ring, respectively.
The asymmetric and symmetric C-O-C stretching modes are expected in the region
-1
1
250-850 cm [33]. The C-O-C stretching modes are reported at 1224, 1160, 1046, 1027
-1
(
DFT), 1171, 1066, 1036 (IR), 1051, 1028 cm (Raman) for 1,3-benzodioxole [18] and at
-1
-1
1
250, 1073 cm [36], 1263, 1055 cm [37]. For the title compound, the C-O-C stretching
-1
-1
modes are observed at 1045, 977 cm in the IR spectrum, 1045, 860 cm in the Raman
-1
spectrum and theoretically at 1047, 974, 863, 850 cm .
The stretching vibrations of the CH group (the asymmetric and symmetric stretch)
2
and the deformation modes (scissoring, wagging, twisting and rocking modes) are expected
-1
in the regions 3050-2850 and 1480-800 cm , respectively [33,38]. The CH stretching modes
2
-1
-1
are assigned at 2976 cm in the IR spectrum, 2973 cm in the Raman spectrum and at 3056,
-1
2
979 cm theoretically. The CH deformation modes are assigned at 1475, 1354, 1116 and
2
-1
1
059 cm theoretically for the title compound as expected [33].
-1
The CH stretching modes are expected in the region 2900-3050 cm [33]. The bands
3
-1
-1
observed at 3020, 2921 cm in the IR spectrum, 3018, 2922 cm in the Raman spectrum and
-1
in the range 3030-2920 cm (DFT) are assigned as the stretching modes of the methyl group.
The methyl asymmetrical deformations are expected in the region 1460±15 and the
-1
symmetrical deformations at 1350±20 cm [33]. The DFT calculation gives these
-1
deformations in the ranges 1479-1442 and 1398-1371 cm as asymmetric and symmetric
deformation modes for the title compound. The deformation modes are observed
-1
experimentally at 1481, 1450, 1396, 1369 cm in the IR spectrum and at 1482, 1450, 1370
-1
cm in the Raman spectrum for the title compound. The methyl rocking vibration has been
-1
-1
expected at 1050±30 and 950±40 cm [33]. The bands observed at 939 cm in the IR
-1
-1
spectrum, 940 cm in the Raman spectrum and in the range 1004-911cm (DFT) are assigned
as the methyl rocking modes.
The tertiary butyl group C(CH ) gives rise to five skeletal deformations absorbing in
3
3
-1
the three regions: δ CC in 435±85, δ CC in 335±80 and ρCC in 300±80 cm [33]. The
as
3
s
3
3
-1
highest (lowest) values for δ CC are observed around 510 (355) cm [30]. Most of the
as
3
-1
δ CC modes have been assigned in the region 435±65 cm [33]. The DFT calculations give
as
3
-1
the values 560, 368 and 368 cm as asymmetric and symmetric deformations. The bands at
-1
3
40 and 293 cm (DFT) are assigned as the rocking modes of the CC . The torsion modes
3
τCH and τCC are expected in the low frequency region [33]. The υ CC and υ CC modes
3
3
as
3
s
3
4

ACCEPTED MANUSCRIPT
-1
are expected in the regions 1235±60 and 800±90 cm , respectively [33]. For the title
-1
compound, the bands observed at 1240 cm in the IR spectrum and theoretically at 1239,
-1
1
204 cm are assigned as the υ CC modes. The DFT calculations give the symmetric υ CC
as 3 s 3
-1
-1
stretching mode at 791 cm and the band observed at 792 cm in the IR spectrum are
assigned as these modes.
-1
According to Socrates [39], the C=C stretching mode is expected around 1600 cm
when conjugated with the C=O group. For the title compound, the band observed at 1523 in
-
1
the IR spectrum, 1540 in the Raman spectrum and theoretically at 1535 cm is assigned as the
-1
C=C stretching mode and the C=O stretching mode is observed at 1624 cm in the Raman
-1
spectrum and theoretically at 1625 cm . For the title compound, the CH modes associated
-1
with the anhyride group are assigned at 3085, 1308, 1222, 1018 cm in the IR spectrum,
-
1
1
8
308, 1019 cm in the Raman spectrum and theoretically at 3087, 3052, 1309, 1225, 1020,
-1
92 cm . The root mean square value between the calculated and observed wavenumbers
were calculated inorder to investigate the performance of the vibrational wavenumbers of the
title compound and the RMS errors are 3.17 for IR bands and 3.39 for Raman bands.
4
.3
Nonlinear optical properties (NLO)
Dipole moment, polarizability and hyperpolarizabilities of organic molecules are
important response properties. There has been an intense investigation for molecules with
large non-zero hyperpolarizabilities, since these substances have potential as the constituents
of nonlinear optical materials. According to the present calculations, the first static
-30
hyperpolarizability calculated β value is found to be 30.75×10 e.s.u which is 236.54 times
-30
that of standard NLO material urea (0.13×10 e.s.u) [40]. The average second
hyperpolarizability is <γ> = (γxxxx + γyyyy + γzzzz + 2γxxyy + 2γxxzz + 2γyyzz)/5. The theoretical
second order hyperpolarizability was calculated using the Gaussian09 software and is equal to
-37
-
14.39×10 e.s.u [41]. We conclude that the title compound is an attractive object for future
studies of nonlinear optical properties.
4
.4
Frontier molecular orbital analysis
The frontier orbital electron densities of atoms can be used as an efficient tool for the
detailed characterization of donor acceptor interactions [42]. The HOMO and LUMO energies
are calculated at the B3LYP/SDD level and the orbitals energy diagrams are shown in Fig. 4.
As can be clearly seen from Fig. 4, the HOMO is over the entire molecule except the methyl
groups, while the LUMO is over the entire molecule except the CH group with the dioxole
2
ring and one of the methyl groups. The chemical reactivity descriptors like chemical potential,
hardness and electrophilicity index are proposed for understanding various aspects of
5

ACCEPTED MANUSCRIPT
pharmacological sciences including drug design and possible eco-toxicological characteristics
of the drugs. Using the HOMO and LUMO orbital energies, the ionization energy and
electron affinity can be expressed as: I = -EHOMO, A = -ELUMO [43]. The hardness η and
chemical potential ꢀ are given the following relations η = (I-A)/2 and ꢀ = - (I+A)/2, where I
and A are the first ionization potential and electron affinity of the chemical species [43]. For
the title compound, the EHOMO = -7.822 eV, ELUMO = -5.770 eV, Energy gap = HOMO-LUMO
=
2.052 eV, Ionization potential I = 7.822 eV, Electron affinity A = 5.770 eV, global hardness
2
η = 1.026 eV, chemical potential ꢀ = -6.796 eV, global electrophiliciy = ꢀ /2η = 22.51 eV. It
is indicative that the chemical potential of the title compound is negative and it means that the
compound is stable.
4
.5
Molecular electrostatic potential (MEP)
The molecular electrostatic potential map yields information on the molecular regions
those are preferred or avoided by an electrophile or nucleophile. Any chemical system creates
an electrostatic potential around itself, when a hypothetical volumeless unit positive charge is
used as a probe, the probe feels the attractive or repulsive forces in regions where the
electrostatic potential is negative or positive, respectively [31]. Molecular electrostatic
potential is found to be a very useful tool in the investigation of the correlation between the
molecular structure and the physiochemical property relationship of the molecules including
biomolecules and drugs [44-49] and it provides a visual method to understand the relative
polarity of the molecule and the different values of the electrostatic potential is represented by
different colors; red, blue and green represent regions of most negative, most positive and
zero electrostatic potential, respectively. The negative (red and yellow) regions of the MEP
were related to electrophilic reactivity and the positive (blue) regions to nucleophilic
reactivity. From the MEP plot (Fig. 5), it is evident that the negative region covers the
carbonyl and C=C groups and the positive region is over CH groups.
2
4
.6
Fukui functions
The Fukui function is a local reactivity descriptor which gives the preferred regions where a
chemical species will change its density when the number of electrons is modified. Hence,
these descriptors indicate the propensity of the electronic density to deform at a given position
upon accepting or donating electrons [50-52]. Also, it is possible to define the corresponding
th
condensed or atomic Fukui functions on the j atom site as,
¯
f = q (N) - q (N-1)
j
j
j
+
f = q (N+1) - q (N)
j
j
j
0
f = ½[q (N+1) - q (N-1)]
j
j
j
6

ACCEPTED MANUSCRIPT
¯
+
For an electrophilic f (r), nucleophilic or free radical attack f (r), on the reference
j
j
molecule, respectively. In these equations, q is the atomic charge (evaluated from Mulliken
j
th
population analysis, electrostatic derived charge, etc.) at the j atomic site is the neutral (N),
anionic (N + 1) or cationic (N - 1) chemical species. Morell et al., [53] have recently proposed
a dual descriptor (∆f(r)), which is defined as the difference between the nucleophilic and
+
¯
electrophilic Fukui function and is given by, ∆f(r) = [f (r) - f (r)]
f(r) > 0, then the site is favored for a nucleophilic attack, whereas if ∆f(r) < 0, then the site
∆
may be favored for an electrophilic attack. The dual descriptors ∆f(r) give a clear difference
between nucleophilic and electrophilic attack at a particular site with their sign and it provide
positive value for site prone for nucleophilic attack and a negative value prone for
electrophilic attack. From the values reported in Table S2(supporting material), according to
the condition for dual descriptor, nucleophilic site for in our title compound is O1, O2, C4,
C5, C8, C10, C12, C14, C15, C16, H17, H18, H19, H20, C28, H29 (positive value i.e. ∆f(r) >
0
). Similarly the electrophilic attack site is O3, C6, C7, C9, C11, C13, H21, H22, H23, H24,
H25, H26, H27, H30, H31, H32, H33(negative value i.e. ∆f(r) < 0). The behavior of
molecules as electrophiles/nucleophiles during reaction depends on the local behavior of
molecules.
4
.7
Natural bond orbital analysis
The natural bond orbitals (NBO) calculations were performed using the NBO 3.1
program [54] as implemented in the Gaussian09 package at the DFT/B3LYP level and the
important results are tabulated in Tables 2 and 3. The important intra-molecular hyper-
conjugative interactions are: n (O )→π*(C -C ), n (O )→π*(C -C ) and n (O )→σ*(C -C )
2
1
5
6
2
2
8
9
2
3
13
14
with stabilization energies 28.81, 27.81 and 21.20 KJ/mol with electron densities 0.37275e,
.34340e and 0.07527e. The natural hybrid orbitals with lower energies and high occupation
numbers are : n (O ), n (O ) and n (O ) with energies, -0.60055, -0.59875, -0.66104 a.u and
0
1
1
1
372
1
3
p-characters, 57.66, 57.45, 43.63% and high occupation numbers, 1.96172, 1.96105, 1.97714
while the orbitals with higher energies and low occupation numbers are: n (O ), n (O ) and
2
1
2
2
n (O ) with energies, -0.33106, -0.32875, -0.24018 a.u and considerable p-characters of 100%
2
3
and low occupation numbers, 1.84600, 1.85769 and 1.88474. Thus, a very close to pure p-
type lone pair orbital participates in the electron donation to the n (O )→π*(C -C ),
2
1
5
6
n (O )→π*(C -C ) and n (O )→σ*(C -C ) interactions in the compound.
2
2
8
9
2
3
13
14
4
.8
Molecular docking
7

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Androgens (ARs) play an important role in the growth of prostate cancer and normal
prostate. Prostate cancer represents the most common male malignancy [55]. Curcumin
analogues were evaluated as potential androgen receptor antagonists against two human
prostate cancer cell lines, PC-3 and DU-145 [56]. ARs and androgen-dependent and
independent signaling pathways has occurred in the context of prostate cancer. However, AR
as a therapeutic target should be explored in other tumors [57, 58]. 1,3-Dioxol derivatives
were reported to exhibits anti-cancer activity against breast cancer cells T47D [59]. High
resolution crystal structure of androgen receptor was downloaded from the protein data bank
website (PDB ID: 1GS4) and all molecular docking calculations were performed on
AutoDock-Vina software [60] and the 3D crystal structure of androgen receptor was obtained
from Protein Data Bank and the protein was prepared for docking by removing the co-
crystallized ligands, waters and co-factors. The Auto Dock Tools (ADT) graphical user
interface was used to calculate Kollman charges and polar hydrogens and the ligand was
prepared for docking by minimizing its energy at the B3LYP/SDD (6D, 10F) level of theory
and the partial charges were calculated by the Geistenger method. The active site of the
enzyme was defined to include the residues of the active site within the grid size of 40 Å × 40
Å × 40 Å and the most popular algorithm, Lamarckian Genetic Algorithm (LGA) available in
.
Autodock was employed for docking. The docking protocol was tested by extracting the co-
crystallized inhibitor from the protein and then docking the same and the docking protocol
predicted the same conformation as was present in the crystal structure with RMSD value
well within the reliable range of 2 Å [61]. Amongst the docked conformations, the one which
binds well at the active site was analyzed for detailed interactions in Discover Studio
Visualizer 4.0 software. The ligand binds at the active site of the substrate (Figs. 6 and 7) by
weak non-covalent interactions. His701 amino acid form H-bond with the C=O group and the
amino acids Gln711, Met745 shows H-bond interaction with the dioxole ring. Phe764 amino
acid indicates π-π interaction with the dioxol and phenyl rings. The amino acids Ala877,
Met780, Leu873, Leu880, His701 and Phe876 form alkyl interaction with the CH groups.
3
Leu707, Met745, Met749 shows π-alkyl interaction with the dioxol and phenyl rings. The
docked ligand title compound forms a stable complex with the androgen receptor (Fig. 8) and
gives a binding affinity (ꢁG in kcal/mol) value of -8.1 (Table 4). These preliminary results
suggest that the compound might exhibit inhibitory activity against androgen receptor.
5
.
Conclusions
8

ACCEPTED MANUSCRIPT
FT-IR and FT-Raman spectra of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
were recorded and analyzed. The vibrational wavenumbers were computed using DFT
quantum chemical calculations and the data obtained from wavenumber calculations were
used to assign the vibrational bands obtained experimentally. A detailed molecular picture of
the title compound and its interactions were obtained from NBO and frontier molecular orbital
analysis. The first and second order hyperpolarizability values are calculated and the first
static hyperpolarizability is found to be 236.54 times that of standard NLO material urea and
hence the title compound and its derivatives are good object for further studies in nonlinear
optics. From the molecular docking study, the ligand binds at the active site of the substrate
by weak non-covalent interactions: His701 amino acid form H-bond with the C=O group and
the amino acids Gln711, Met745 shows H-bond interaction with the dioxole ring. Phe764
amino acid indicates π-π interaction with the dioxol and phenyl rings and the amino acids
Ala877, Met780, Leu873, Leu880, His701 and Phe876 form alkyl interaction with the CH3
groups and Leu707, Met745, Met749 shows π-alkyl interaction with the dioxol and phenyl
rings. The geometrical parameters theoretically obtained are in good agreement with the
reported XRD data.
Acknowledgements
The authors would like to extend their sincere appreciation to the Deanship of
Scientific Research at King Saud University for funding this work through the Research
Group Project No. RGP-VPP-196. The authors are thankful to University of Antwerp for
access to the University’s CalcUA Supercomputer Cluster.
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Figure captions
Fig. 1: FT-IR spectrum of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
Fig. 2: FT-Raman spectrum of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
1
2

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Fig. 3: Optimized geometry of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
Fig. 4: HOMO-LUMO plots of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
Fig. 5: MEP plot of (E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-one
Fig. 6: The interactive plot of ligand and androgen receptor
Fig. 7: The docked protocol reproduced the co-crystallized conformation wth H-bond (green),
π-alkyl (pink), π-π (magenta) and H-bond receptor surface shown
Fig. 8: Schematic for the docked conformation of active site of the title compound at
androgen receptor
1
3

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Table 1
Calculated (scaled) wavenumbers, observed IR, Raman bands and assignments of the title
compound
a
B3LYP/SDD (6D, 10F)
IR
Raman
Assignments
-
-
1
-1
-1
υ(cm )
IRI
RA
υ(cm )
υ(cm )
3
3
3
3
3
3
3
3
3
3
3
3
2
2
2
2
1
1
1
1
1
1
1
1
1
1
126
123
089
087
056
052
030
018
014
010
007
004
979
932
922
920
625
599
581
535
479
475
468
463
463
452
4.00 173.60
4.94 2.44
-
3124
υCHPh(99)
-
-
υCHPh(97)
15.97 31.34
6.76 36.63
29.35 135.86
0.24 26.12
38.20 57.43
78.27 162.26
73.15 53.80
9.39 14.08
48.84 88.41
4.84 11.17
126.06 283.00
40.06 330.81
21.90 185.13
33.71 4.39
-
-
υCH(17), υCHPh(81)
υCH(79), υCHPh(17)
3085
-
-
-
υCH (100)
2
-
-
υCH(97)
-
-
υCH (98)
3
3020
3018
υCH (92)
3
-
-
3
υCH (96)
-
-
υCH (98)
3
-
-
3
υCH (90)
-
-
υCH (100)
3
2976
2973
υCH (100)
2
-
-
2 3
υCH (42), υCH (46)
-
-
υCH (94)
3
2921
2922
3
υCH (98)
185.52 1026.73
9.31 626.31
20.57 102.84
323.29 1956.98
50.59 6.16
-
1624
υC=O(54), υC=C(13)
υPh(68)
1605
1595
1585
-
υPh(66)
1523
1540
υC=C(59), υC=O(12)
1481
1482
3
δCH (85)
7.05 38.31
18.20 21.35
162.90 26.41
9.43 20.07
0.78 16.57
-
-
-
-
-
-
-
-
-
-
δCH (91)
2
δCH (86)
3
δCHPh(27), υPh(54)
δCH (89)
3
3
δCH (92)
1

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1
1
1
1
1
1
1
1
1
1
450
442
425
398
375
371
359
354
309
296
0.02 15.05
0.59 2.91
208.45 386.20
37.24 37.98
14.99 1.43
14.92 0.27
46.30 8.66
9.20 51.71
6.38 180.74
28.45 10.16
1450
1450
3
δCH (90)
-
-
δCH (92)
3
-
1419
υPh(48), δCHPh(21)
1396
-
3
δCH (92)
-
-
δCH (94)
3
1369
1370
3
δCH (96)
-
-
υPh(47), δCH (16)
2
-
-
δCH (67)
2
1308
-
1308
-
δCH(57), υPh(22)
δCH(18), υCC(15),
δCHPh(17), υPh(10)
1
1
1
1
1
1
254
239
225
204
187
180
8.94 0.69
38.87 81.69
319.43 156.60
10.53 5.04
6.21 7.28
43.12 7.94
1258
1240
1222
-
1256
δCHPh(50), δCH (28)
3
-
υCC(57), δCH (12)
3
-
δCH(47), υCO(21), υPh(10)
-
υCC(49), δCH (20)
3
1191
-
1188
-
3
δCH (25), υCC(47)
δCHPh(43), υCO(13),
υCC(11)
1
1
1
1
1
1
1
9
9
9
9
9
9
117
116
070
059
047
020
004
99
47.32 13.68
0.01 8.39
159.90 60.87
6.30 1.39
71.45 135.17
29.80 6.03
10.58 3.82
96.32 66.08
161.25 4.07
3.60 0.99
0.01 0.19
6.45 2.92
0.70 15.69
1120
-
δCHPh(47), υPh(26)
-
1114
δCH (99)
2
1072
1072
3
υCC(34), δPh(20), δCH (15)
-
-
δCH (99)
2
1045
1045
δPh(32), υCO(50)
1018
1019
γCH(43), τC=C(22)
-
-
δCH (56), γCH(11)
3
-
-
3
δCH (63), υCC(18)
74
977
-
υCO(72), γCHPh(11)
γCHPh(82)
49
-
951
940
-
43
939
3
δCH (81)
23
-
-
υCC(13), υPh(10), δCH (46)
3
20
-
3
υCC(19), δCH (48)
2

ACCEPTED MANUSCRIPT
9
8
8
8
8
8
7
7
7
7
7
6
5
5
5
5
4
4
4
3
3
3
3
2
2
2
2
2
2
1
11
92
80
63
50
24
91
69
32
25
01
76
97
94
60
11
97
30
26
68
68
55
40
93
78
32
24
19
03
99
3.48 5.87
0.52 8.87
22.78 4.16
15.33 9.72
51.16 6.56
51.94 0.45
1.95 5.36
7.35 47.01
2.66 0.31
4.36 5.21
0.18 0.17
0.26 11.75
6.76 0.35
0.63 10.93
0.34 17.13
21.16 1.15
12.41 3.77
4.65 0.41
4.91 0.20
0.27 0.23
5.11 1.02
0.01 2.90
7.09 0.71
7.58 3.02
0.90 0.26
0.04 1.49
0.32 0.70
0.06 0.61
0.08 0.16
0.08 2.85
-
-
3
υCC(46), δCH (40)
-
-
γCHPh(24), γCH(59)
γCHPh(63), γCH(12)
υCC(13), υCO(47)
882
-
-
-
-
860
υCO(72), γCHPh(12)
γCHPh(84)
830
828
792
-
υCC(45), δPh(11)
764
766
υPh(49), υCO(20), δPh(13)
τPh(60), γCC(11), γC=O(10)
δCO(29), δPh(33)
733
735
-
722
-
-
γC=O(30), τPh(29)
δCO(59), δPh(11)
-
-
-
-
γCC(32), τPh(43), τCO(12)
τCO(31), δPh(25)
592
593
-
-
δCC(45), δC=O(15)
δPh(10), δCC(50), δC=O(11)
δPh(46), δCC(19)
518
515
-
-
-
-
δPh(18), δCC(48)
428
424
2
τPh(26), δCH (30)
-
-
-
-
-
-
-
-
-
-
-
367
δCC(62), τPh(18)
δCC(39), δPh(26)
τPh(66)
367
-
-
δCC(62), δC=O(16)
δCC(75)
-
-
δCC(61), γC=O(13)
τPh(50), τCO(21)
-
-
τCH (92)
3
215
-
τCH (69)
3
2
τPh(51), τCO(14), τCH (20)
197
δC=C(17), δCC(39), δPh(11),
τCH (22)
2
3

ACCEPTED MANUSCRIPT
1
1
1
6
73
50
16
9
0.33 2.68
0.10 0.04
0.10 2.73
5.74 0.10
-
-
-
-
170
-
δCC(65), δC=C(11)
τCH (89)
3
118
-
τCC(28), γC=O(26), δCC(14)
τCC(20), τCO(21), γCC(11),
τCH (39)
2
5
3
2
5
2
9
8
0.39 1.13
0.45 1.17
15.15 2.17
0.22 1.29
-
-
-
-
-
-
-
-
δCC(65), δC=C(28)
τCO(59), τCC(14)
τCO(87)
1
τCO(54), τCC(18)
a
υ-stretching; δ-in-plane deformation; γ-out-of-plane deformation;τ -torsion; Ph-phenyl ring;
potential energy distribution (%) is given in brackets in the assignment column; IRI-IR intensity;
R -Raman activity.
A
4

ACCEPTED MANUSCRIPT
Table 2
Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intramolecular
bonds of the title compound.
a
b
c
Donor(i)
Type ED/e
Acceptor(j) Type ED/e
E(2)
5.30
5.18
E(j)-E(i)
1.41
1.42
0.30
0.30
1.31
1.32
0.31
0.30
1.15
1.31
1.04
1.26
0.85
1.14
0.35
0.84
1.13
0.36
1.12
1.05
0.70
0.63
F(ij)
O1-C7
σ
σ
π
-
1.98871
C5-C6
σ*
σ*
π*
σ*
σ*
σ*
π*
π*
σ*
σ*
σ*
σ*
σ*
σ*
π*
σ*
σ*
π*
σ*
σ*
σ*
σ*
0.02124
0.01923
0.37659
0.01923
0.02124
0.01923
0.37659
0.37275
0.02179
0.01296
0.01795
0.01296
0.02923
0.03996
0.37275
0.03074
0.03996
0.34340
0.05902
0.07527
0.05902
0.07527
0.077
0.077
0.070
0.068
0.066
0.069
0.066
0.070
0.062
0.053
0.033
0.041
0.051
0.062
0.096
0.051
0.061
0.094
0.042
0.038
0.106
0.104
O2-C7
1.98901
C8-C9
C5-C6
1.68487
C4-C10
C8-C9
19.45
19.32
4.24
-
-
C6-C8
σ
-
1.97755
C5-C6
-
-
C8-C9
4.46
C8-C9
π
-
1.72057
C4-C10
C5-C6
17.09
19.58
4.25
-
-
C12-C13
σ
-
1.98108
C10-C11
C11-C12
C14-C15
C11-C12
O2-C7
-
-
2.71
-
-
-
1.33
C13-C14
σ
σ
-
1.97304
1.96172
-
1.68
LPO1
3.83
-
C6-C8
4.25
-
π
σ
-
1.84600
1.96105
-
C5-C6
28.81
3.94
LPO2
O1-C7
-
C6-C8
4.14
-
π
σ
-
1.85769
1.97714
-
C8-C9
27.81
1.91
LPO3
C12-C13
C13-C14
C12-C13
C13-C14
-
-
1.67
π
-
1.88474
-
19.52
21.20
-
a
E(2) means energy of hyper-conjugative interactions (stabilization energy in kJ/mol)
b
Energy difference (a.u) between donor and acceptor i and j NBO orbitals
F(i,j) is the Fock matrix elements (a.u) between i and j NBO orbitals
c
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Table 3
NBO results showing the formation of Lewis and non-Lewis orbitals.
a
Bond(A-B) ED/e
EDA%
EDB%
NBO
0.8259(sp )O+
s%
p%
2
.90
σO1-C7
1.98871
68.21
31.79
25.63 74.37
21.30 78.70
25.78 74.22
21.52 78.48
0.00 100.0
0.00 100.0
34.39 65.61
34.29 65.71
0.00 100.0
0.00 100.0
32.38 67.62
34.81 65.19
35.16 64.84
24.09 75.91
42.34 57.66
3
.68
-
-0.82137
1.98901
-0.82302
1.68487
-0.27165
1.97755
-0.72263
1.72057
-0.27320
-
-
0.5638(sp )C
2
.88
σ O2-C7
68.05
31.95
0.8249(sp )O+
3
.63
-
-
-
0.5653(sp )C
1
.00
π C5-C6
51.47
48.53
0.7174(sp )C+
1
.00
-
-
-
0.6966(sp )C
1
.91
σ C6-C8
49.99
50.01
0.7070(sp )C+
1
.92
-
-
-
0.7072(sp )C
1
.00
π C8-C9
49.55
50.45
0.7039(sp )C+
1
.00
-
-
-
0.7103(sp )C
2
.09
σ C12-C13 1.98108
-0.64307
σ C13-C14 1.97304
51.64
48.36
0.7186(sp )C+
1
.87
-
-
-
0.6954(sp )C
1
.84
48.05
51.95
0.6932(sp )C+
3
.15
-
-0.59757
1.96172
-0.60055
1.84600
-0.33106
1.96105
-0.59875
1.85769
-0.32875
1.97714
-0.66104
1.88474
-0.24018
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.7207(sp )C
1
1
1
1
0
1
.36
.00
.35
.00
.77
.00
n1O1
sp
-
-
-
-
n2O1
sp
-
0.00 100.0
-
-
-
n1O2
sp
-
42.55 57.45
-
-
-
n2O2
sp
-
0.00 100.0
-
-
-
n1O3
sp
-
56.37 43.63
-
-
-
n2O3
-
sp
-
0.00 100.0
-
-
a
ED/e in a.u.
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Table 4
The binding affinity values of different poses of the title compound
predicted by Autodock Vina.
Mode Affinity (kcal/mol) Distance from best mode (Å)
-
-
RMSD l.b.
0.000
RMSD u.b.
0.000
1
2
3
4
5
6
7
8
9
-8.1
-7.6
-7.3
-7.1
-5.6
-5.5
-5.5
-5.1
-5.1
1.015
2.107
1.559
7.080
1.380
7.097
12.701
1.456
13.823
6.988
12.910
12.770
10.130
13.830
14.309
11.672
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