Privileged Scaffold Chalcone: Synthesis, Characterization and Its Mechanistic Interaction Studies with BSA Employing Spectroscopic and Chemoinformatics Approaches
Identifieur interne : 000002 ( Pmc/Corpus ); précédent : 000001; suivant : 000003Privileged Scaffold Chalcone: Synthesis, Characterization and Its Mechanistic Interaction Studies with BSA Employing Spectroscopic and Chemoinformatics Approaches
Auteurs : Nidhi Singh ; Neeraj Kumar ; Garima Rathee ; Damini Sood ; Aarushi Singh ; Vartika Tomar ; Sujata K. Dass ; Ramesh ChandraSource :
- ACS Omega [ 2470-1343 ] ; 2020.
Abstract
Chalcone, a privileged structure, is considered as an effective template in the field of medicinal chemistry for potent drug discovery. In the present study, a privileged template chalcone was designed, synthesized, and characterized by various spectroscopic techniques (NMR, high-resolution mass spectrometry, Fourier transform infrared (FT-IR) spectroscopy, UV spectroscopy, and single-crystal X-ray diffraction). The mechanism of binding of chalcone with bovine serum albumin (BSA) was determined by multispectroscopic techniques and computational methods. Steady-state fluorescence spectroscopy suggests that the intrinsic fluorescence of BSA was quenched upon the addition of chalcone by the combined dynamic and static quenching mechanism. Time-resolved spectroscopy confirms complex formation. FT-IR and circular dichroism spectroscopy suggested the presence of chalcone in the BSA molecule microenvironment and also the possibility of rearrangement of the native structure of BSA. Moreover, molecular docking studies confirm the moderate binding of chalcone with BSA and the molecular dynamics simulation analysis shows the stability of the BSA–drug complex system with minimal deformability fluctuations and potential interaction by the covariance matrix. Moreover, pharmacodynamics and pharmacological analysis show good results through Lipinski rules, with no toxicity profile and high gastrointestinal absorptions by boiled egg permeation assays. This study elucidates the mechanistic profile of the privileged chalcone scaffold to be used in therapeutic applications.
Url:
DOI: 10.1021/acsomega.9b03479
PubMed: 32064388
PubMed Central: 7016911
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PMC:7016911Le document en format XML
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<author><name sortKey="Singh, Nidhi" sort="Singh, Nidhi" uniqKey="Singh N" first="Nidhi" last="Singh">Nidhi Singh</name>
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<author><name sortKey="Kumar, Neeraj" sort="Kumar, Neeraj" uniqKey="Kumar N" first="Neeraj" last="Kumar">Neeraj Kumar</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry,<institution>University of Delhi</institution>
, Delhi 110007,<country>India</country>
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<author><name sortKey="Rathee, Garima" sort="Rathee, Garima" uniqKey="Rathee G" first="Garima" last="Rathee">Garima Rathee</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry,<institution>University of Delhi</institution>
, Delhi 110007,<country>India</country>
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<author><name sortKey="Sood, Damini" sort="Sood, Damini" uniqKey="Sood D" first="Damini" last="Sood">Damini Sood</name>
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, Delhi 110007,<country>India</country>
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<front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="ao9b03479_0009" id="ab-tgr1"></graphic>
</p>
<p>Chalcone,
a privileged structure, is considered as an effective
template in the field of medicinal chemistry for potent drug discovery.
In the present study, a privileged template chalcone was designed,
synthesized, and characterized by various spectroscopic techniques
(NMR, high-resolution mass spectrometry, Fourier transform infrared
(FT-IR) spectroscopy, UV spectroscopy, and single-crystal X-ray diffraction).
The mechanism of binding of chalcone with bovine serum albumin (BSA)
was determined by multispectroscopic techniques and computational
methods. Steady-state fluorescence spectroscopy suggests that the
intrinsic fluorescence of BSA was quenched upon the addition of chalcone
by the combined dynamic and static quenching mechanism. Time-resolved
spectroscopy confirms complex formation. FT-IR and circular dichroism
spectroscopy suggested the presence of chalcone in the BSA molecule
microenvironment and also the possibility of rearrangement of the
native structure of BSA. Moreover, molecular docking studies confirm
the moderate binding of chalcone with BSA and the molecular dynamics
simulation analysis shows the stability of the BSA–drug complex
system with minimal deformability fluctuations and potential interaction
by the covariance matrix. Moreover, pharmacodynamics and pharmacological
analysis show good results through Lipinski rules, with no toxicity
profile and high gastrointestinal absorptions by boiled egg permeation
assays. This study elucidates the mechanistic profile of the privileged
chalcone scaffold to be used in therapeutic applications.</p>
</div>
</front>
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</TEI>
<pmc article-type="research-article" xml:lang="EN"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">ACS Omega</journal-id>
<journal-id journal-id-type="iso-abbrev">ACS Omega</journal-id>
<journal-id journal-id-type="publisher-id">ao</journal-id>
<journal-id journal-id-type="coden">acsodf</journal-id>
<journal-title-group><journal-title>ACS Omega</journal-title>
</journal-title-group>
<issn pub-type="epub">2470-1343</issn>
<publisher><publisher-name>American Chemical Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32064388</article-id>
<article-id pub-id-type="pmc">7016911</article-id>
<article-id pub-id-type="doi">10.1021/acsomega.9b03479</article-id>
<article-categories><subj-group><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Privileged Scaffold Chalcone: Synthesis, Characterization
and Its Mechanistic Interaction Studies with BSA Employing Spectroscopic
and Chemoinformatics Approaches</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="ath1"><name><surname>Singh</surname>
<given-names>Nidhi</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath2"><name><surname>Kumar</surname>
<given-names>Neeraj</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath3"><name><surname>Rathee</surname>
<given-names>Garima</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath4"><name><surname>Sood</surname>
<given-names>Damini</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath5"><name><surname>Singh</surname>
<given-names>Aarushi</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath6"><name><surname>Tomar</surname>
<given-names>Vartika</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath7"><name><surname>Dass</surname>
<given-names>Sujata K.</given-names>
</name>
<xref rid="aff2" ref-type="aff">‡</xref>
</contrib>
<contrib contrib-type="author" corresp="yes" id="ath8"><name><surname>Chandra</surname>
<given-names>Ramesh</given-names>
</name>
<xref rid="cor1" ref-type="other">*</xref>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="aff3" ref-type="aff">§</xref>
</contrib>
<aff id="aff1"><label>†</label>
Department of Chemistry,<institution>University of Delhi</institution>
, Delhi 110007,<country>India</country>
</aff>
<aff id="aff2"><label>‡</label>
<institution>BLK Super Speciality Hospital</institution>
, Pusa Road, Delhi, New Delhi 110005,<country>India</country>
</aff>
<aff id="aff3"><label>§</label>
Dr. B. R. Ambedkar Center for Biomedical Research,<institution>University of Delhi</institution>
, Delhi 110007,<country>India</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
E-mail: <email>acbrdu@hotmail.com</email>
, <email>rameshchandragroup@gmail.com</email>
.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>27</day>
<month>01</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><day>11</day>
<month>02</month>
<year>2020</year>
</pub-date>
<volume>5</volume>
<issue>5</issue>
<fpage>2267</fpage>
<lpage>2279</lpage>
<history><date date-type="received"><day>18</day>
<month>10</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>15</day>
<month>01</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2020 American Chemical Society</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>American Chemical Society</copyright-holder>
<license><license-p>This is an open access article published under an ACS AuthorChoice <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/page/policy/authorchoice_termsofuse.html">License</ext-link>
, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.</license-p>
</license>
</permissions>
<abstract><p content-type="toc-graphic"><graphic xlink:href="ao9b03479_0009" id="ab-tgr1"></graphic>
</p>
<p>Chalcone,
a privileged structure, is considered as an effective
template in the field of medicinal chemistry for potent drug discovery.
In the present study, a privileged template chalcone was designed,
synthesized, and characterized by various spectroscopic techniques
(NMR, high-resolution mass spectrometry, Fourier transform infrared
(FT-IR) spectroscopy, UV spectroscopy, and single-crystal X-ray diffraction).
The mechanism of binding of chalcone with bovine serum albumin (BSA)
was determined by multispectroscopic techniques and computational
methods. Steady-state fluorescence spectroscopy suggests that the
intrinsic fluorescence of BSA was quenched upon the addition of chalcone
by the combined dynamic and static quenching mechanism. Time-resolved
spectroscopy confirms complex formation. FT-IR and circular dichroism
spectroscopy suggested the presence of chalcone in the BSA molecule
microenvironment and also the possibility of rearrangement of the
native structure of BSA. Moreover, molecular docking studies confirm
the moderate binding of chalcone with BSA and the molecular dynamics
simulation analysis shows the stability of the BSA–drug complex
system with minimal deformability fluctuations and potential interaction
by the covariance matrix. Moreover, pharmacodynamics and pharmacological
analysis show good results through Lipinski rules, with no toxicity
profile and high gastrointestinal absorptions by boiled egg permeation
assays. This study elucidates the mechanistic profile of the privileged
chalcone scaffold to be used in therapeutic applications.</p>
</abstract>
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<meta-value>ao9b03479</meta-value>
</custom-meta>
<custom-meta><meta-name>document-id-new-14</meta-name>
<meta-value>ao9b03479</meta-value>
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<custom-meta><meta-name>ccc-price</meta-name>
<meta-value></meta-value>
</custom-meta>
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</article-meta>
</front>
<body><sec id="sec1"><title>Introduction</title>
<p>Serum albumins are
one of the major soluble protein components
present in the circulatory system that perform numerous physiological
functions, including regulation of osmotic pressure, maintenance of
blood pH, and distribution and transportation of various endogenous
and exogenous molecules such as drugs, food additives, etc.<sup><xref ref-type="bibr" rid="ref1">1</xref>
−<xref ref-type="bibr" rid="ref7">7</xref>
</sup>
The approximate concentration of serum albumin in human blood is
3.6–5.2 g/dL, which can be increased up to double.<sup><xref ref-type="bibr" rid="ref8">8</xref>
</sup>
The drug or ligand molecule binds with albumin
either weakly or strongly. A stronger binding of a drug molecule with
albumin leads to a decrease of concentration of the drug in plasma,
while the weakly bounded drug has a shorter lifetime and poor distribution
in plasma.<sup><xref ref-type="bibr" rid="ref9">9</xref>
,<xref ref-type="bibr" rid="ref10">10</xref>
</sup>
The degree of interaction between drug and
serum albumin is an important factor for any molecule being a commercial
drug as the binding interaction study decides the drug lifetime, its
solubility, and distribution in plasma.<sup><xref ref-type="bibr" rid="ref11">11</xref>
</sup>
</p>
<p>Bovine serum albumin (BSA) is about 76% sequential analogs
to human
serum albumin (HSA).<sup><xref ref-type="bibr" rid="ref12">12</xref>
</sup>
BSA is considered
as a model protein for deciphering the interaction between different
small ligand molecules and albumins due to its low cost, easy availability,
and structure homology with HSA.<sup><xref ref-type="bibr" rid="ref13">13</xref>
−<xref ref-type="bibr" rid="ref15">15</xref>
</sup>
BSA consists of three
structurally homolog domains (I–III), and each domain is further
split into two subdomains, named A and B.<sup><xref ref-type="bibr" rid="ref9">9</xref>
</sup>
The drug-binding sites of serum albumin are commonly located in
the hydrophobic cavity of subdomains IIA and IIIA, which are known
as Sudlow’s sites I and II, respectively.<sup><xref ref-type="bibr" rid="ref16">16</xref>
,<xref ref-type="bibr" rid="ref17">17</xref>
</sup>
X-ray crystallographic data reveal that the major difference between
BSA and HSA is that HSA contained only one tryptophan-Trp-214, while
BSA consists of two tryptophans (Trp-134 and Trp-213). Trp-134 is
positioned on the surface of the protein and is present in subdomain
IB, while Trp-213 is trapped within the hydrophobic pocket of the
protein and is present in subdomain IIA.<sup><xref ref-type="bibr" rid="ref1">1</xref>
</sup>
</p>
<p>Chalcone is a simple and common chemical scaffold of many
biologically
active compounds isolated from natural sources. This privileged structure
has attracted research attention for a century.<sup><xref ref-type="bibr" rid="ref18">18</xref>
</sup>
The common scaffold present in chalcones is 1,3-diaryl-2-propen-1-one,
commonly called chalconoid, which exists in two isomeric forms (cis
and trans), with the trans form found to be more thermodynamically
stable.<sup><xref ref-type="bibr" rid="ref19">19</xref>
,<xref ref-type="bibr" rid="ref20">20</xref>
</sup>
There are two phenyl rings in chalcone derivatives.
In this research article, the phenyl ring which is attached to the
carbonyl group is named ring A, while the other benzene ring is defined
as ring B (<xref rid="fig1" ref-type="fig">Figure <xref rid="fig1" ref-type="fig">1</xref>
</xref>
).</p>
<fig id="fig1" position="float"><label>Figure 1</label>
<caption><p>The structure of chalcone.</p>
</caption>
<graphic xlink:href="ao9b03479_0014" id="gr1" position="float"></graphic>
</fig>
<p>Chalcones belong to a class of potential lead compounds that act
as an effective template in novel drug discovery in medicinal chemistry.
The synthetic protocol for developing a new chalcone is very easy
and environmentally feasible. Synthetic and natural chalcones show
various therapeutic applications such as antidiabetic, anti-inflammatory,
anticancer, antioxidant, anti-infective, or antiproliferative activities.<sup><xref ref-type="bibr" rid="ref21">21</xref>
−<xref ref-type="bibr" rid="ref27">27</xref>
</sup>
However, the exact mechanism of action for various pharmacological
effects of chalcones is not discovered yet.</p>
<p>In 2006, Kuo-Hsiung
Lee and his group reported that the 2-hydroxy-3-methoxy
chalcone showed significant activity against the human tumor cancer
cell line (lung carcinoma A549).<sup><xref ref-type="bibr" rid="ref28">28</xref>
</sup>
A simple
chalcone molecule possessing only hydroxyl and methoxy substituents
exhibits a good NF-kB inhibitory activity, and thus acts as a potential
anticancer agent.<sup><xref ref-type="bibr" rid="ref29">29</xref>
</sup>
The replacement of
hydrogen by halogen can effectively change the biological property
of the drug. The substitution of hydrogen by chlorine in trimethoxy
chalcone significantly improves the anticancer activity, which is
due to the electromeric effect provided by the chlorine group being
located at the 4′ position (para position to the carbonyl group)
of the phenyl ring.<sup><xref ref-type="bibr" rid="ref30">30</xref>
</sup>
Various quinolinyl
chalcone derivatives were tested for biological activity against the
Plasmodium falciparum strain. The hypoxanthine uptake by strain of
P. falciparum (chloroquine-resistant strain) was mostly inhibited
by quinolinyl chalcone bearing chloro-substituted benzoyl ring.<sup><xref ref-type="bibr" rid="ref31">31</xref>
</sup>
More research is needed to develop potent therapeutic
agents, which can prove effective against multidrug-resistant strains.</p>
<p>By considering the structure–activity relationship study
of chalcones reported in the literature, we have designed to synthesize
the chalcone “(<italic>E</italic>
)-1-(2,4-dichlorophenyl)-3-(2-hydroxy-3-methoxyphenyl)prop-2-en-1-one”.
To the best of my knowledge, only single-crystal X-ray diffraction
(XRD) study of this compound has been reported so far.<sup><xref ref-type="bibr" rid="ref32">32</xref>
</sup>
It is essential to study the biodistribution
of the drug in blood plasma, which directs the development of effective
strategies for their safe medical use.<sup><xref ref-type="bibr" rid="ref33">33</xref>
</sup>
The binding mechanism between drug and albumin is an effective tool
to understand the pharmacokinetic property of the drug properly. Some
previous studies have reported the mode of binding interaction of
chalcone with BSA.<sup><xref ref-type="bibr" rid="ref34">34</xref>
−<xref ref-type="bibr" rid="ref38">38</xref>
</sup>
In the present study, a new chalcone derivative incorporating a
chlorine substituent in ring A and hydroxyl and methoxy substituents
in ring B was designed, synthesized, and well characterized by various
spectroscopic techniques (NMR, high-resolution mass spectrometry (HRMS),
FT-IR spectroscopy, UV spectroscopy, and single-crystal XRD). The
interaction study of chalcone with BSA has been investigated by employing
various multispectroscopic techniques such as UV–vis, steady-state
fluorescence, time-resolved fluorescence, FT-IR, and circular dichroism
(CD) spectroscopy. Molecular modeling studies, including molecular
docking and molecular dynamics simulation studies, are also employed
to assess the potency and binding mechanism of the drug with target
proteins.<sup><xref ref-type="bibr" rid="ref39">39</xref>
−<xref ref-type="bibr" rid="ref41">41</xref>
</sup>
Theoretical studies are well employed to assess the
potency and absorption studies of the drug.<sup><xref ref-type="bibr" rid="ref42">42</xref>
,<xref ref-type="bibr" rid="ref43">43</xref>
</sup>
Also, pharmacokinetic and pharmacodynamic analyses have been carried
out for the complete assessment of drugs for high absorption, excretion,
and no toxicity profiles or side effects. Computational values are
reported in many studies to follow the Lipinski rule of five and drug
likeliness. The pharmacological and pharmacodynamic profiles of compounds
are well converted to develop effective therapeutic agents.<sup><xref ref-type="bibr" rid="ref44">44</xref>
−<xref ref-type="bibr" rid="ref46">46</xref>
</sup>
</p>
</sec>
<sec id="sec2"><title>Results and Discussion</title>
<sec id="sec2.1"><title>Single-Crystal XRD Analysis</title>
<p>The
chalcone C<sub>16</sub>
H<sub>12</sub>
Cl<sub>2</sub>
O<sub>3</sub>
belongs
to the monoclinic
system with space group <italic>P</italic>
2<sub>1</sub>
/<italic>n</italic>
. The observed cell parameters are <italic>a</italic>
= 11.5245(10)
Å, <italic>b</italic>
= 3.9894(3) Å, <italic>c</italic>
=
31.742(2) Å, α = 90°, β = 96.235(7)°, γ
= 90°, and V = 1450.7(2) Å<sup>3</sup>
. The data which relate
the structural refinement to information about the collection of data
are presented in <xref rid="tbl1" ref-type="other">Table <xref rid="tbl1" ref-type="other">1</xref>
</xref>
. The ORTEP diagram obtained from the XRD data is presented in <xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
, which closely resembles
the diagram reported in the literature.<sup><xref ref-type="bibr" rid="ref32">32</xref>
</sup>
The obtained bond length and bond angle are listed in <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Table S1</ext-link>
.</p>
<fig id="fig2" position="float"><label>Figure 2</label>
<caption><p>Molecular structure of C01 is presented
in the ellipsoid style
at the 50% probability level. The hydrogen atom is shown as a fixed
sphere of radius 0.17 Å, and the bond style is of stick type
with radius 0.1 Å.</p>
</caption>
<graphic xlink:href="ao9b03479_0001" id="gr2" position="float"></graphic>
</fig>
<table-wrap id="tbl1" position="float"><label>Table 1</label>
<caption><title>Crystal Data and Structural Refinement
Parameter of C<sub>16</sub>
H<sub>12</sub>
Cl<sub>2</sub>
O<sub>3</sub>
</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="left"></col>
</colgroup>
<tbody><tr><td style="border:none;" align="left">empirical formula</td>
<td style="border:none;" align="left">C<sub>16</sub>
H<sub>12</sub>
Cl<sub>2</sub>
O<sub>3</sub>
</td>
</tr>
<tr><td style="border:none;" align="left">crystal shape/color</td>
<td style="border:none;" align="left">needle/yellow</td>
</tr>
<tr><td style="border:none;" align="left">formula weight</td>
<td style="border:none;" align="left">323.16</td>
</tr>
<tr><td style="border:none;" align="left">temperature (K)</td>
<td style="border:none;" align="left">293(2)</td>
</tr>
<tr><td style="border:none;" align="left">crystal system</td>
<td style="border:none;" align="left">monoclinic</td>
</tr>
<tr><td style="border:none;" align="left">space group</td>
<td style="border:none;" align="left"><italic>P</italic>
2<sub>1</sub>
/<italic>n</italic>
</td>
</tr>
<tr><td rowspan="6" style="border:none;" align="left">cell parameters</td>
<td style="border:none;" align="left"><italic>a</italic>
= 11.5245(10)
Å</td>
</tr>
<tr><td style="border:none;" align="left"><italic>b</italic>
= 3.9894(3)
Å</td>
</tr>
<tr><td style="border:none;" align="left"><italic>c</italic>
= 31.742(2)
Å</td>
</tr>
<tr><td style="border:none;" align="left">α = 90°</td>
</tr>
<tr><td style="border:none;" align="left">β = 96.235(7)°</td>
</tr>
<tr><td style="border:none;" align="left">γ = 90°</td>
</tr>
<tr><td style="border:none;" align="left">volume</td>
<td style="border:none;" align="left">1450.7(2) Å<sup>3</sup>
</td>
</tr>
<tr><td style="border:none;" align="left"><italic>Z</italic>
</td>
<td style="border:none;" align="left">4</td>
</tr>
<tr><td style="border:none;" align="left">density (g/cm<sup>3</sup>
)</td>
<td style="border:none;" align="left">1.480</td>
</tr>
<tr><td style="border:none;" align="left">μ (mm<sup>–1</sup>
)</td>
<td style="border:none;" align="left">0.454</td>
</tr>
<tr><td style="border:none;" align="left"><italic>F</italic>
(000)</td>
<td style="border:none;" align="left">664</td>
</tr>
<tr><td style="border:none;" align="left">temperature (K)</td>
<td style="border:none;" align="left">293</td>
</tr>
<tr><td style="border:none;" align="left">crystal size (mm<sup>3</sup>
)</td>
<td style="border:none;" align="left">0.07 × 0.06 ×
0.01</td>
</tr>
<tr><td style="border:none;" align="left">radiation</td>
<td style="border:none;" align="left">Mo Kα (λ = 0.71073)</td>
</tr>
<tr><td style="border:none;" align="left">absorption correction</td>
<td style="border:none;" align="left">multiscan</td>
</tr>
<tr><td style="border:none;" align="left">index ranges</td>
<td style="border:none;" align="left">–14 ≤ <italic>h</italic>
≤ 14, −4 ≤ <italic>k</italic>
≤
4, −39 ≤ <italic>l</italic>
≤ 39</td>
</tr>
<tr><td style="border:none;" align="left">reflections collected</td>
<td style="border:none;" align="left">17 651</td>
</tr>
<tr><td style="border:none;" align="left">independent reflections</td>
<td style="border:none;" align="left">2940 (<italic>R</italic>
<sub>int</sub>
= 0.0466, <italic>R</italic>
<sub>sigma</sub>
= 0.0345)</td>
</tr>
<tr><td style="border:none;" align="left">data/restraints/parameters</td>
<td style="border:none;" align="left">2940/0/238</td>
</tr>
<tr><td style="border:none;" align="left">goodness of fit on <italic>F</italic>
<sup>2</sup>
</td>
<td style="border:none;" align="left">1.091</td>
</tr>
<tr><td style="border:none;" align="left">final <italic>R</italic>
indexes (<italic>I</italic>
≥ 2σ
(<italic>I</italic>
))</td>
<td style="border:none;" align="left"><italic>R</italic>
<sub>1</sub>
= 0.0469, w<italic>R</italic>
<sub>2</sub>
= 0.1000</td>
</tr>
<tr><td style="border:none;" align="left">final <italic>R</italic>
indexes (all data)</td>
<td style="border:none;" align="left"><italic>R</italic>
<sub>1</sub>
= 0.0662, w<italic>R</italic>
<sub>2</sub>
= 0.1114</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec2.2"><title>UV–Visible Absorption
Spectroscopy Analysis</title>
<p>The UV–visible absorption measurement
is a very simple and
valuable technique to analyze the formation of a complex between drug
and protein. The absorption spectra of pure BSA have an only characteristic
peak around 280 nm, which represents the π–π* transition
due to the presence of aromatic amino acids (tyrosine, tryptophan,
and phenylalanine).<sup><xref ref-type="bibr" rid="ref47">47</xref>
</sup>
The peak intensity
of BSA increased with the addition of chalcone (<xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref>
</xref>
), which inferred the interaction between
chalcone and BSA.</p>
<fig id="fig3" position="float"><label>Figure 3</label>
<caption><p>UV–visible absorption spectra of pure BSA and BSA
in the
presence of different concentrations of C01. [BSA] = 15 μM,
[C01] = (a) 0 μM, (b) 1.5 μM, (c) 3.0 μM, (d) 4.5
μM, (e) 6.0 μM, (f) 7.5 μM, (g) 9.0 μM.</p>
</caption>
<graphic xlink:href="ao9b03479_0002" id="gr3" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.3"><title>Fluorescence Spectroscopy Analysis</title>
<p>Steady-state fluorescence
spectroscopy is the most effective and valuable technique to decipher
the mechanism of interaction between protein (HSA/BSA) and drug molecule.<sup><xref ref-type="bibr" rid="ref48">48</xref>
−<xref ref-type="bibr" rid="ref50">50</xref>
</sup>
The fluorescent nature of the BSA molecule, which is mainly due
to the presence of the tryptophan, phenylalanine, and tyrosine residues,
is often used as a fluorescent probe to study the alteration in the
conformation of BSA on the addition of the drug.<sup><xref ref-type="bibr" rid="ref51">51</xref>
,<xref ref-type="bibr" rid="ref52">52</xref>
</sup>
Out of the three residues, Trp has the highest fluorescence intensity,
which contributes more to fluorescence quenching of the protein. The
two Trp residues, Trp-134 and Trp-213, are present in the BSA molecule.
The former one is present on the surface, while the latter is located
in the hydrophobic pocket of the BSA molecule.<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
</p>
<p>The fluorescence spectra of the BSA solution in the
absence and presence of chalcone are shown in <xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref>
</xref>
. The BSA solution showed the emission maximum
at 340 nm, when the excitation wavelength was kept at 280 nm. The
fluorescence emission intensity of the BSA solution decreased regularly
on the successive addition of chalcone without any significant change
in the emission maximum wavelength. This observation suggests the
changes in the BSA molecule microenvironment due to interaction with
chalcone, and the chalcone binds into the binding cavity of the BSA
molecule.</p>
<fig id="fig4" position="float"><label>Figure 4</label>
<caption><p>Steady-state fluorescence emission spectra of BSA and its fluorescence
quenching spectra in the presence of varying concentration of C01
at 298 K. [BSA] = 15 μM, [C01] = 0, 1.0, 2.0, 3.0, 4.0, 5.0,
6.0, 7.0, 8.0, 9.0 μM.</p>
</caption>
<graphic xlink:href="ao9b03479_0012" id="gr4" position="float"></graphic>
</fig>
<p>The fluorescence quenching of the protein is classified into three
quenching mechanisms, namely, static quenching mechanism, dynamic
quenching mechanism, and the combination of the static and dynamic
quenching mechanisms. The static quenching mechanism refers to the
ground-state complex between the drug and protein, the dynamic quenching
mechanism resulted from the collision of protein with the drug molecule,
and the combined quenching refers to both collision encounter of the
protein with the drug and the complex formation between the protein
and drug.<sup><xref ref-type="bibr" rid="ref53">53</xref>
−<xref ref-type="bibr" rid="ref56">56</xref>
</sup>
</p>
<p>The Stern–Volmer plot and the double-logarithmic plot
of
the BSA–C01 complex system are shown in <xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref>
</xref>
A,B, respectively. The Stern–Volmer
constant (<italic>K</italic>
<sub>SV</sub>
) was determined by using <xref rid="eq4" ref-type="disp-formula">eq <xref rid="eq4" ref-type="disp-formula">4</xref>
</xref>
. The quenching rate constant
(<italic>k</italic>
<sub>q</sub>
) of the BSA–C01 complex system
is simply calculated by considering the τ<sub>o</sub>
value
equal to 10<sup>–8</sup>
s.<sup><xref ref-type="bibr" rid="ref57">57</xref>
</sup>
The
calculated value of <italic>k</italic>
<sub>q</sub>
≫ 2.0 ×
10<sup>10</sup>
M<sup>–1</sup>
s<sup>–1</sup>
indicates
the presence of the static quenching mechanism (the maximum scattering
collision quenching rate constant value is 2.0 × 10<sup>10</sup>
M<sup>–1</sup>
s<sup>–1</sup>
).<sup><xref ref-type="bibr" rid="ref58">58</xref>
</sup>
</p>
<fig id="fig5" position="float"><label>Figure 5</label>
<caption><p>(A) Stern–Volmer plot of <italic>F</italic>
<sub>0</sub>
/<italic>F</italic>
versus [C01] for fluorescence quenching spectra of BSA
upon addition of C01 at 298 K. (B) Plot of log[(<italic>F</italic>
<sub>0</sub>
– <italic>F</italic>
)/<italic>F</italic>
] versus
log[C01] for the BSA–C01 complex system at 298 K.</p>
</caption>
<graphic xlink:href="ao9b03479_0005" id="gr5" position="float"></graphic>
</fig>
<p>The value of binding constant (<italic>K</italic>
<sub>b</sub>
)
and the binding stoichiometry (<italic>n</italic>
) of chalcone in
the protein molecule are calculated using <xref rid="eq5" ref-type="disp-formula">eq <xref rid="eq5" ref-type="disp-formula">5</xref>
</xref>
and are represented in <xref rid="tbl2" ref-type="other">Table <xref rid="tbl2" ref-type="other">2</xref>
</xref>
. The binding constant value (<italic>K</italic>
<sub>b</sub>
) is found to be 1.60 × 10<sup>5</sup>
M<sup>–1</sup>
, and the binding stoichiometry (<italic>n</italic>
) is nearly equal
to 1.</p>
<table-wrap id="tbl2" position="float"><label>Table 2</label>
<caption><title>Quenching Constant (<italic>k</italic>
<sub>q</sub>
), Binding Constant (<italic>K</italic>
<sub>b</sub>
),
and the Binding Stoichiometry (<italic>n</italic>
) of Chalcone in
the BSA Molecule Microenvironment at 298 K</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">code</th>
<th style="border:none;" align="center"><italic>T</italic>
(K)</th>
<th style="border:none;" align="center"><italic>K</italic>
<sub>SV</sub>
(M<sup>–1</sup>
)</th>
<th style="border:none;" align="center"><italic>k</italic>
<sub>q</sub>
(M<sup>–1</sup>
s<sup>–1</sup>
)</th>
<th style="border:none;" align="center"><italic>r</italic>
<sup>2</sup>
</th>
<th style="border:none;" align="center"><italic>K</italic>
<sub>b</sub>
(M<sup>–1</sup>
)</th>
<th style="border:none;" align="center"><italic>n</italic>
</th>
<th style="border:none;" align="center"><italic>r</italic>
<sup>2</sup>
</th>
</tr>
</thead>
<tbody><tr><td style="border:none;" align="left">C01</td>
<td style="border:none;" align="left">298</td>
<td style="border:none;" align="left">7.96 × 10<sup>4</sup>
</td>
<td style="border:none;" align="left">7.96 × 10<sup>12</sup>
</td>
<td style="border:none;" align="left">0.9934</td>
<td style="border:none;" align="left">1.60 × 10<sup>5</sup>
</td>
<td style="border:none;" align="left">1.06</td>
<td style="border:none;" align="left">0.9899</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec2.4"><title>Time-Resolved
Fluorescence Spectroscopy Analysis</title>
<p>The
lifetime decay measurement is considered as an ideal nanoscale detection
method. The emission measurement of the BSA molecule is highly influenced
by the presence of other interacting molecules in the lifetime measurement.<sup><xref ref-type="bibr" rid="ref59">59</xref>
</sup>
Time-resolved measurement is used to distinguish
between different modes of quenching: static, dynamic, and mixed quenching
modes. The fluorescence decay profile was recorded for the BSA solution
in the absence and presence of chalcone (C01) (<xref rid="fig6" ref-type="fig">Figure <xref rid="fig6" ref-type="fig">6</xref>
</xref>
). The lifetime value of the fluorescence
decay profile of BSA in the absence and presence of C01 is presented
in <xref rid="tbl3" ref-type="other">Table <xref rid="tbl3" ref-type="other">3</xref>
</xref>
. The dynamic
quenching constant (<italic>K</italic>
<sub>D</sub>
) is obtained from
lifetime measurement by using <xref rid="eq1" ref-type="disp-formula">eq <xref rid="eq1" ref-type="disp-formula">1</xref>
</xref>
<disp-formula id="eq1"><graphic xlink:href="ao9b03479_m001" position="anchor"></graphic>
<label>1</label>
</disp-formula>
where τ<sub>o</sub>
is the lifetime
of the BSA solution in the absence of C01, τ is the lifetime
of the BSA solution in the presence of C01, and the concentration
of C01 is represented by [Q].</p>
<fig id="fig6" position="float"><label>Figure 6</label>
<caption><p>Lifetime decay profile of pure BSA and BSA in
the presence of C01
in phosphate-buffered saline (PBS) (pH = 7.4). [BSA] = 15 μM
and [C01] = 8 μM.</p>
</caption>
<graphic xlink:href="ao9b03479_0013" id="gr6" position="float"></graphic>
</fig>
<table-wrap id="tbl3" position="float"><label>Table 3</label>
<caption><title>Lifetime
Obtained from the Fluorescence
Decay Profile of BSA and the BSA–C01 System</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">concentration</th>
<th style="border:none;" align="center" char=".">τ<sub>1</sub>
(ns)</th>
<th style="border:none;" align="center" char=".">τ<sub>2</sub>
(ns)</th>
<th style="border:none;" align="center" char="."><italic>a</italic>
<sub>1</sub>
</th>
<th style="border:none;" align="center" char="."><italic>a</italic>
<sub>2</sub>
</th>
<th style="border:none;" align="center" char=".">τ<sub>av</sub>
(ns)</th>
</tr>
</thead>
<tbody><tr><td style="border:none;" align="left">BSA</td>
<td style="border:none;" align="char" char=".">2.57</td>
<td style="border:none;" align="char" char=".">6.39</td>
<td style="border:none;" align="char" char=".">25.21</td>
<td style="border:none;" align="char" char=".">74.79</td>
<td style="border:none;" align="char" char=".">5.43</td>
</tr>
<tr><td style="border:none;" align="left">BSA + 8 μM C01</td>
<td style="border:none;" align="char" char=".">2.12</td>
<td style="border:none;" align="char" char=".">5.95</td>
<td style="border:none;" align="char" char=".">35.69</td>
<td style="border:none;" align="char" char=".">64.31</td>
<td style="border:none;" align="char" char=".">4.58</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>The value
of dynamic quenching constant obtained from <xref rid="eq1" ref-type="disp-formula">eq <xref rid="eq1" ref-type="disp-formula">1</xref>
</xref>
is 2.3 × 10<sup>4</sup>
M<sup>–1</sup>
. <xref rid="eq2" ref-type="disp-formula">Equation <xref rid="eq2" ref-type="disp-formula">2</xref>
</xref>
is used
to calculate the value of static quenching constant.<sup><xref ref-type="bibr" rid="ref60">60</xref>
</sup>
<disp-formula id="eq2"><graphic xlink:href="ao9b03479_m002" position="anchor"></graphic>
<label>2</label>
</disp-formula>
The plot of the graph [(<italic>F</italic>
<sub>0</sub>
– <italic>F</italic>
)/<italic>F</italic>
]/[Q]
versus [Q] gives the value of static quenching constant. The value
of <italic>K</italic>
<sub>S</sub>
(3.7 × 10<sup>4</sup>
M<sup>–1</sup>
) is greater than that of <italic>K</italic>
<sub>D</sub>
. The difference between <italic>K</italic>
<sub>S</sub>
and <italic>K</italic>
<sub>D</sub>
is not too large. Hence, this result indicates
that C01 did not induce the quenching of protein (BSA) by a single
quenching mechanism. The combined static and dynamic quenching exists
in the C01–BSA system. A change in the absorption spectra of
BSA was observed upon addition of C01, and the value of the quenching
rate constant (7.96 × 10<sup>12</sup>
M<sup>–1</sup>
s<sup>–1</sup>
) is greater than the maximum collision quenching
rate constant (2.0 × 10<sup>10</sup>
M<sup>–1</sup>
s<sup>–1</sup>
). All such observations indicate that the predominately
static quenching exists in the BSA–C01 system.</p>
</sec>
<sec id="sec2.5"><title>FT-IR Spectra
Analysis</title>
<p>To probe a deep insight into
the binding interaction of chalcone with BSA, FT-IR spectra were analyzed.
Proteins exhibit two bands in the infrared region. The amide I band
in the region 1600–1700 cm<sup>–1</sup>
is mainly due
to C=O stretching vibration of the amide moiety, whereas the
amide II band, which lies in the region 1500–1600 cm<sup>–1</sup>
, is due to the C–N stretching vibration in combination with
the N–H bending mode. The amide I band is normally more susceptible
to change in the secondary structure of protein (BSA) than the amide
II band.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
While adding C01 into the BSA
solution, the transmittance intensity of the IR spectra of BSA decreased
slightly and the peak positions of the amide I and II bands showed
minor shifts from 1640 to 1638 and from 1541 to 1539, respectively
(<xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref>
</xref>
). This result
indicated the presence of chalcone in the BSA microenvironment.</p>
<fig id="fig7" position="float"><label>Figure 7</label>
<caption><p>FT-IR spectra
of (A) pure BSA solution and (B) BSA in the presence
of C01. [BSA] = 1 × 10<sup>–4</sup>
M, [C01] = 1 ×
10<sup>–4</sup>
M.</p>
</caption>
<graphic xlink:href="ao9b03479_0006" id="gr7" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.6"><title>CD Analysis</title>
<p>Circular dichroism analysis has been performed
to observe the secondary structure conformational changes in BSA upon
addition of chalcone (C01). <xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref>
</xref>
shows the CD spectra of pure BSA and the BSA:C01 complex.
The circular dichroism spectra of pure BSA are obtained in phosphate
buffer (pH = 7.4) at 298 K. The spectra exhibited two negative minima
located at 208 and 222 nm due to the characteristic α helical
structural unit present in the protein.<sup><xref ref-type="bibr" rid="ref54">54</xref>
</sup>
The bands at 208 and 222 nm correspond to the π → π*
and n → π* transitions of the α helix.<sup><xref ref-type="bibr" rid="ref57">57</xref>
,<xref ref-type="bibr" rid="ref62">62</xref>
</sup>
Upon the addition of chalcone to the BSA solution, the intensity
of the minima at 208 and 222 nm in the CD spectrum of pure BSA decreased
slightly. The α-helix content residing in the secondary structure
of BSA shows a very less decrease upon addition of chalcone (<xref rid="tbl4" ref-type="other">Table <xref rid="tbl4" ref-type="other">4</xref>
</xref>
), which indicates
the little change in the secondary structure of BSA.<sup><xref ref-type="bibr" rid="ref63">63</xref>
</sup>
In other words, the protein BSA has retained its native
secondary α- helical structure even after binding the drug.<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
</p>
<fig id="fig8" position="float"><label>Figure 8</label>
<caption><p>Circular dichroism spectra of BSA in the absence and presence
of
different concentrations of C01 in phosphate-buffered saline (PBS)
(pH = 7.4). [BSA] = 5 μM and [C01] = 5 μM.</p>
</caption>
<graphic xlink:href="ao9b03479_0010" id="gr8" position="float"></graphic>
</fig>
<table-wrap id="tbl4" position="float"><label>Table 4</label>
<caption><title>Value of α-Helix % Obtained
from the Interaction between BSA and Chalcone (C01)</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="char" char="."></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">concentration</th>
<th style="border:none;" align="center" char=".">α-helix
(%)</th>
</tr>
</thead>
<tbody><tr><td style="border:none;" align="left">pure BSA</td>
<td style="border:none;" align="char" char=".">32.7</td>
</tr>
<tr><td style="border:none;" align="left">BSA–C01 (ratio 1:1)</td>
<td style="border:none;" align="char" char=".">31.5</td>
</tr>
<tr><td style="border:none;" align="left">BSA–C01 (ratio 1:5)</td>
<td style="border:none;" align="char" char=".">32.2</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec2.7"><title>Three-Dimensional (3D) Crystal Structure Retrieval of Bovine
Serum Albumin and Assessment</title>
<p>Three-dimensional (3D) crystal
structure of BSA was retrieved from the Protein Data Bank with PDB
ID 4OR0 and 2.58 Å resolution. The BSA structure consists of
two chains of A and B of size 583 amino acid residues and in conjugation
with drug naproxen. Structural parameters and stereochemical properties
of the BSA structure were evaluated by the Ramachandran plot, which
provides information about the dihedral angles and the amino acid
residues region, whether in favorable/unfavorable regions. The result
showed that 92.8% of amino acid residues lie in the allowed region
and 7.2% lie in the additionally allowed region with no amino acids
in the outlier region (<xref rid="fig9" ref-type="fig">Figure <xref rid="fig9" ref-type="fig">9</xref>
</xref>
). Local quality estimation showed that the BSA structure
is stable with many fluctuations (0.38–0.98 Å deviations)
with native structures. Also, verified 3D server elucidated the high
quality of the BSA crystal structure by depicting that the BSA structure
has more than 80% amino acid residues with optimal 3D/1D profiles
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Figure S1</ext-link>
). Furthermore, Errat server
also confirmed the high quality of BSA with major residues underlying
the warning region and showed the high resolution of the structure.
Assessment results of the BSA structure confirmed its high quality
to be used for further studies.</p>
<fig id="fig9" position="float"><label>Figure 9</label>
<caption><p>(A) Three-dimensional crystal structure
of bovine serum albumin,
retrieved from the Protein Data Bank, (B) Ramachandran plot of BSA
protein, which showed that 92.7% amino acid residues lie in the favorable
region and 7.2% lie in the additionally allowed region. (C) Local
quality estimation plot of the BSA protein, showing minimal fluctuations
of residues (<1 Å).</p>
</caption>
<graphic xlink:href="ao9b03479_0003" id="gr9" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.8"><title>Molecular Docking Studies of Chalcone with BSA</title>
<p>Molecular
docking was performed to evaluate the binding potential of C01 with
the BSA protein. Autodock was set on the interaction of 3D conformations
of the target BSA protein, and the grid dimensions were made to 0.6
Å with a receptor and ligand range of 180°, which was followed
by a BSA protein flip and twist range of 360°. The molecular
docking process followed the translational steps to determine the
high energy scoring functions for various ligand-binding conformations
to the target protein BSA. Among the resulting 1000 complex systems,
the top five clusters with high binding energy scoring functions were
assessed. Chalcone interacts with the binding groove of the BSA protein
at high-energy confinements, and the highest docking score was found
to be −5.79 kJ/mol by Autodock (<xref rid="fig10" ref-type="fig">Figure <xref rid="fig10" ref-type="fig">10</xref>
</xref>
). Moreover, to validate our results, we
have redocked the C01 with BSA using the Hex 8.0 software. It was
set to shape and steric conformations interaction study using the
fast Fourier mode. BSA grid dimensions were set at 0.6 Å, as
provided by the docking manual and followed by the BSA protein flip
and a twist range of 360°. From the output 25 interacting complexes,
one with the highest docking score (−192.99 kJ/mol) was found,
which was further analyzed to determine the involved molecular interactions
using the Ligplot (<xref rid="fig11" ref-type="fig">Figure <xref rid="fig11" ref-type="fig">11</xref>
</xref>
). Ligplot showed the strong hydrophobic interaction of the
C01 with BSA with the involvement of amino acids: Leu 24, Lys 132,
His 145, Leu 189, Ser 128, Ile 455. These results suggested the moderate
binding of C01 under study to the BSA protein at two regions: one
at 24–189 and the second at the 428–455 amino acid region
of BSA.</p>
<fig id="fig10" position="float"><label>Figure 10</label>
<caption><p>Binding energy conformations of drug to the BSA protein with scoring
functions. (A) The closest binding with the highest docking score
of −5.79 kJ/mol, (B) binding of drug with the second most high
energy score of −5.73 kJ/mol, (C) binding energy conformations
of drug to BSA with −5.50 kJ/mol, (D) binding conformations
of drug to BSA with a score of −5.47 kJ/mol, (E) binding conformations
with a score of −5.39 kJ/mol, and (F) binding conformations
with minimal interaction of drug to the BSA with a score of −5.37
kJ/mol. The drug is shown in gray, and BSA is shown in orange.</p>
</caption>
<graphic xlink:href="ao9b03479_0004" id="gr10" position="float"></graphic>
</fig>
<fig id="fig11" position="float"><label>Figure 11</label>
<caption><p>(Left) Depiction of molecular interactions of C01 to the
binding
groove of the BSA protein and (right) depiction of molecular interactions
involved in the C01–BSA complex.</p>
</caption>
<graphic xlink:href="ao9b03479_0007" id="gr11" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.9"><title>Molecular Dynamics Simulation Study of the C01–BSA Complex</title>
<p>The C01–BSA complex was assessed for large-scale flexibility
and its stability using the normal mode analysis (NMA). I-Mod simulation
server was employed to study the internal coordinating molecules of
the complex. The resulted complex trajectory was analyzed for the
deformation to define its stability. Trajectory showed that the C01–BSA
complex is stable with minimal deformability fluctuations (0.1–1
Å) by protein hinge distortion analysis. Trajectory files are
also found to be similar to the normal mode analysis reference protein
with minimal atomic fluctuations (<xref rid="fig12" ref-type="fig">Figure <xref rid="fig12" ref-type="fig">12</xref>
</xref>
). The Eigen score is obtained to be 1.354970
× 10<sup>–5</sup>
, and the variance of normal mode is
the inversion of this score (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Figure S2</ext-link>
),
which signified the rigidity of the C01–BSA complex. After
that, an elastic network and covariance matrix analysis was performed
using the complex trajectory. The covariance matrix stated the coupling
of C01-protein atoms; correlated, noncorrelated, and uncorrelated
atomic fluctuations are shown by red, blue, and white colors in the
figure, respectively. The elastic model shows the atomic pairs through
the strings of complex, individual dots show the one sting by degree
of stiffness with the corresponding atomic pairs, and dark gray stings
show the rigidity and stability of the C01–BSA complex.</p>
<fig id="fig12" position="float"><label>Figure 12</label>
<caption><p>Simulation
trajectory analysis of C01–BSA complex. (A) Plot
depicting the atomic fluctuations and showing the minimal deformability
complex. (B) Comparison of a complex system with normal mode analysis
complex as a reference, indicating fewer atomic fluctuations. (C)
Covariance matrix and (D) elastic network analysis; the results signify
the higher rigidity of the complex system and higher stability of
the complex with a minimal deformation index.</p>
</caption>
<graphic xlink:href="ao9b03479_0008" id="gr12" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.10"><title>Bioavailability Absorption Analysis of Drug by Boiled Egg Permeation</title>
<p>Boiled egg permeation assay was performed to assess the drug efficacy
for high bioavailability and high gastrointestinal absorption. It
is an intuitive graphical analysis for the passive absorption of the
compound through the intestine and blood–brain barrier. The
result showed that chalcone is falling inside the yellow ellipse (yolk),
which indicated high values for permeation through the blood–brain
barrier. Moreover, chalcone was found to pass through the white ellipse,
which suggested the high intestinal absorption of the chalcone, according
to the defined algorithm of permeation assay (<xref rid="fig13" ref-type="fig">Figure <xref rid="fig13" ref-type="fig">13</xref>
</xref>
).</p>
<fig id="fig13" position="float"><label>Figure 13</label>
<caption><p>(A) Depiction of parameters of the Lipinski
rule of five for chalcone.
(B) Graphical representation of chalcone absorption through the boiled
egg permeation assay.</p>
</caption>
<graphic xlink:href="ao9b03479_0011" id="gr13" position="float"></graphic>
</fig>
</sec>
<sec id="sec2.11"><title>Pharmacological and Toxicity
Profiling of the Chalcone</title>
<p>Pharmacological analysis of chalcone
was performed to assess the
physicochemical potency and toxicity profile. The result showed that
chalcone followed the Lipinski rule of five (requisite parameters
for druggability). Chalcone has a molecular weight of 323.17 g/mol,
partition coefficient value (log <italic>P</italic>
) of 4.603,
three hydrogen-bond acceptors, one hydrogen-bond donor group, and
a surface area of 46.53 A<sup>2</sup>
. Importantly, the compound was
obtained to be highly absorbed in intestine with 91.91% oral absorption
values with a good water solubility; it is a primary site of absorption
of the drugs, and absorption <30% is considered to be poorly absorbed.<sup><xref ref-type="bibr" rid="ref64">64</xref>
</sup>
The skin permeability value was obtained to
be −2.80 log <italic>K</italic>
<sub>p</sub>
.
The volume of distribution parameter was also studied to determine
the drug concentration in plasma, and it showed that chalcone is less
absorbed with a score of −0.017 and an available unbound fraction
of 0.055 fraction unit.<sup><xref ref-type="bibr" rid="ref65">65</xref>
</sup>
Moreover, the
maximum recommended daily dose of chalcone was assessed through the
local weighed approach, which showed that chalcone has a high tolerated
daily dose with a score of 0.489 log mg/kg/day. Also, toxicity profiling
and side-effects analyses were performed, as these are important aspects
to consider during the design and development of the drug. Toxicity
profile analysis showed that chalcone is noncarcinogenic, as confirmed
by the negative output of the Ames test. Moreover, the relative toxicity
of chalcone was analyzed by assessing the acute toxicity lethal dosage
value (LD50). The LD50 value demonstrates the concentration of drug
dose that may cause the death of 50% of animals under investigation.
The results showed an LD50 value of 2.346 log mg/kg and the oral rat
chronic toxicity score of 1.403 log mg/kg per day with no skin sensations.
These results illustrated the no toxicity and side effects associated
with administration of chalcone.</p>
</sec>
</sec>
<sec id="sec3"><title>Conclusions</title>
<p>This
study summarizes the synthesis, characterization, and mechanistic
interaction of chalcone with serum protein (BSA) using spectroscopic
and chemoinformatics approaches. Chalcone effectively quenched the
intrinsic fluorescence of BSA by a combined static and dynamic quenching
mechanism. The quenching of fluorescence intensity of BSA was mainly
caused by the complex formation of chalcone with BSA. FT-IR and CD
spectroscopy experiments revealed the potential interaction of chalcone
and BSA with no disturbance to the native structure of BSA and the
physiological function of the serum protein. Moreover, in silico studies
validated the moderate binding of chalcone with BSA, in correlation
with spectroscopic data. Molecular docking and molecular dynamic simulation
studies suggested the stabile binding of chalcone with the BSA microenvironment.
The pharmacological and pharmacodynamics results add on druggability
of the chalcone to be used in therapeutic applications.</p>
</sec>
<sec id="sec4"><title>Materials and
Methods</title>
<sec id="sec4.1"><title>Chemicals and Reagents</title>
<p>All of the chemicals are used
as obtained commercially without any purification. <sup>1</sup>
H and <sup>13</sup>
C NMR spectra were recorded on a Jeol JNM ECX-400P spectrometer
at 400 and 100 MHz, respectively. NMR spectra of the compound were
obtained in CDCl<sub>3</sub>
, considering tetramethylsilane as an
internal standard. High-resolution mass spectra (HRMS) were recorded
on an Agilent 6520 Q-TOF mass spectrometer. Single-crystal XRD was
obtained using an X-Calibur instrument. The UV–vis absorption
measurement was carried out using a CARY 300 Conc UV–visible
spectrophotometer. Fluorescence spectra were recorded on a Horiba
PTI QM-8450-11-C. The lifetime decay spectra were recorded using Horiba
PTI QM-8450-11-C. The FT-IR spectral analysis was carried out using
an IR Affinity-1S, Shimadzu Fourier transform infrared spectrophotometer.
A JASCO J-185 CD spectrometer was used to record the CD spectra.</p>
</sec>
<sec id="sec4.2"><title>Synthesis of Chalcone (C01)</title>
<p>The synthetic route of
the target chalcone is presented in <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Scheme S1</ext-link>
using ref (<xref ref-type="bibr" rid="ref66">66</xref>
). To
a solution of 2,4-dichloroacetophenone (0.01 mol) and ortho-vanillin
(0.01 mol) in ethanol (13 ml) was added an aqueous solution of 40%
NaOH (3.0 ml) in a dropwise manner. Then, the reaction mixture was
refluxed at 60 °C. After 12 h, the solution was poured into ice-cold
water, then the suspension was quenched with 2 M HCl to make the mixture
acidic. The organic layer was extracted with ethyl acetate, then washed
with water and brine. The organic layer was dried over anhydrous sodium
sulfate, concentrated in vacuo, and then purified by silica gel column
chromatography to give the target compound <bold>C01</bold>
(yellow
needle-shaped crystal). <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
): δ 7.72 (1H, d, <italic>J</italic>
= 16.2 Hz), 7.46 (1H,
d, <italic>J</italic>
= 1.9 Hz), 7.42 (1H, d, <italic>J</italic>
=
8.2 Hz), 7.33 (1H, dd, <italic>J</italic>
= 8.2, 2.0 Hz), 7.25 (1H,
d, <italic>J</italic>
= 16.2 Hz), 7.12 (1H, dd, <italic>J</italic>
= 7.4, 2.1 Hz), 6.83–6.90 (2H, m), 6.19 (1H, s), 3.90 (3H,
s). <sup>13</sup>
C NMR (101 MHz, CDCl<sub>3</sub>
): δ 193.35,
146.93, 145.94, 141.89, 137.74, 136.72, 132.49, 130.51, 130.24, 127.25,
126.98, 121.21, 120.72, 119.94, 112.52, 56.32. HRMS (EI) <italic>m</italic>
/<italic>z</italic>
Calculated for C<sub>16</sub>
H<sub>12</sub>
Cl<sub>2</sub>
O<sub>3</sub>
322.0163; Observed (M + H)<sup>+</sup>
323.0228.
UV-309 nm. The <sup>1</sup>
H NMR, <sup>13</sup>
C NMR, HRMS, UV, and
FT-IR spectra are provided in the supporting information (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Figures S3–S7</ext-link>
). The scanning electron
microscopy (SEM) images of chalcone (C01) and normal chalcone without
modification are also provided in the Supporting Information (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">Figure S8</ext-link>
).</p>
</sec>
<sec id="sec4.3"><title>X-ray Crystallography</title>
<p>Single-crystal data of chalcone
(C01) were collected by using the X-Calibur instrument of Oxford Diffraction
Ltd. (λ = 0.71073 Å, Mo Kα radiation). OLEX 2 software
was used to determine all of the geometric parameters, and mercury
software packages were used to obtain the image of the compound.<sup><xref ref-type="bibr" rid="ref67">67</xref>
,<xref ref-type="bibr" rid="ref68">68</xref>
</sup>
</p>
</sec>
<sec id="sec4.4"><title>Binding of Chalcone with BSA</title>
<sec id="sec4.4.1"><title>Preparation of Solutions</title>
<p>The purity
of the BSA was
verified by determining its absorbance at 280 nm. The stock solution
of 15 μM BSA was prepared in 10 mM phosphate-buffered saline
(PBS, pH = 7.4). The stock solution of 2.5 mM chalcone was prepared
in acetonitrile. The volume/volume ratio of acetonitrile/PBS was less
than 1%, and at this volume percentage, the acetonitrile does not
affect the structure of BSA.<sup><xref ref-type="bibr" rid="ref69">69</xref>
</sup>
All of the
spectroscopic experiments were carried out at 298 K.</p>
</sec>
<sec id="sec4.4.2"><title>Absorbance
Measurements</title>
<p>The UV–vis absorption
measurement for both pure BSA solution and the BSA–C01 complex
were recorded in the range of 200–400 nm at 298 K. The reference
solution used in the UV measurement was phosphate-buffered saline
(PBS, 10 mM, pH = 7.4). The concentration of BSA was made constant
at 15 μM, whereas the concentration of C01 was varied from 0
to 9 μM with an interval of 1.5 μM.</p>
</sec>
<sec id="sec4.4.3"><title>Steady-State
Fluorescence Measurement</title>
<p>The fluorescence
emission spectra of both BSA and the BSA–C01 complex were obtained
in the wavelength range of 290–500 nm at 298 K. The excitation–emission
slit width was kept at 3 nm, and the excitation wavelength was fixed
at 280 nm for all of the emission measurements. For the titration,
the concentration of BSA was made constant at 15 μM, and the
C01 varied from 0 to 9 μM with an interval of 1 μM for
the BSA–C01 complex. While the C01 solution was being added
into the BSA solution, the fluorescence quenching of BSA was observed.</p>
<p>The fluorescence quenching of serum protein (BSA) was also attributed
to the absorbance of ultraviolet radiation by the drug at the excitation
wavelength (280 nm) and emission wavelength (340 nm). This inner filter
effect from the drug was compensated by correcting the steady-state
fluorescence spectra using <xref rid="eq3" ref-type="disp-formula">eq <xref rid="eq3" ref-type="disp-formula">3</xref>
</xref>
(<xref ref-type="bibr" rid="ref70">70</xref>
,<xref ref-type="bibr" rid="ref71">71</xref>
)<disp-formula id="eq3"><graphic xlink:href="ao9b03479_m003" position="anchor"></graphic>
<label>3</label>
</disp-formula>
where <italic>F</italic>
<sub>cor</sub>
and <italic>F</italic>
<sub>obs</sub>
are the corrected and observed fluorescence
intensity values, respectively, while <italic>A</italic>
<sub>ex</sub>
and <italic>A</italic>
<sub>em</sub>
are the absorbance values of
the drug at excitation and emission wavelengths, respectively.</p>
<p>The binding mechanism of the BSA–C01 complex was determined
by the Stern–Volmer equation (<xref rid="eq4" ref-type="disp-formula">eq <xref rid="eq4" ref-type="disp-formula">4</xref>
</xref>
)<disp-formula id="eq4"><graphic xlink:href="ao9b03479_m004" position="anchor"></graphic>
<label>4</label>
</disp-formula>
where <italic>F</italic>
<sub>0</sub>
is the
fluorescence intensity of the pure BSA solution, <italic>F</italic>
is the fluorescence intensity of the BSA solution after the addition
of chalcone, [Q] denotes the concentration of chalcone, <italic>K</italic>
<sub>SV</sub>
is the Stern–Volmer association constant, <italic>k</italic>
<sub>q</sub>
is the quenching rate constant of the biomolecular
reaction, and τ<sub>o</sub>
is the average lifetime of the BSA
in the absence of the chalcone.</p>
<p>The fluorescence quenching data
of the BSA were evaluated to determine
the binding parameters like binding constant (<italic>K</italic>
<sub>b</sub>
) and the number of binding sites (<italic>n</italic>
) for
chalcone in the BSA environment by using <xref rid="eq5" ref-type="disp-formula">eq <xref rid="eq5" ref-type="disp-formula">5</xref>
</xref>
<disp-formula id="eq5"><graphic xlink:href="ao9b03479_m005" position="anchor"></graphic>
<label>5</label>
</disp-formula>
</p>
</sec>
<sec id="sec4.4.4"><title>Time-Resolved
Fluorescence Measurement</title>
<p>The time-correlated
single photon counting technique is utilized to perform the time-resolved
fluorescence measurement to record the fluorescence decay profile
with a high resolution.<sup><xref ref-type="bibr" rid="ref72">72</xref>
</sup>
The BSA molecule
was excited using a nanosecond pulsed light-emitting diode source
(pulse width, 1.2 nm; pulse repetition rate, 1 MHz).<sup><xref ref-type="bibr" rid="ref43">43</xref>
</sup>
Fluorescence lifetime is derived from the fluorescence
decay profile.<sup><xref ref-type="bibr" rid="ref73">73</xref>
</sup>
The fluorescence decay
profile was recorded for pure BSA solution (15 μM) and BSA solution
in the presence of chalcone. The excitation and emission wavelengths
were fixed at 280 and 340 nm, respectively. The scattering of Ludox
solution was measured regularly to determine the instrument response
function.<sup><xref ref-type="bibr" rid="ref74">74</xref>
</sup>
</p>
</sec>
</sec>
<sec id="sec4.5"><title>FT-IR Measurement</title>
<p>The IR spectra of pure BSA and BSA–C01
system (1:1 ratio) were acquired in the wavelength range of 1000–1900
cm<sup>–1</sup>
, while the FT-IR spectra of pure chalcone were
obtained in the wavelength range of 480–4000 cm<sup>–1</sup>
at 298 K. The IR spectra of the free BSA solution were obtained
by subtracting the spectra of the buffer solution from the spectra
of the protein solution. The difference absorbance spectra of BSA
were obtained after subtracting the spectra of the pure chalcone solution
from the spectra of the chalcone–BSA solution.</p>
</sec>
<sec id="sec4.6"><title>Circular Dichroism
Measurement</title>
<p>The CD spectra of the
BSA solution in the absence and presence of different concentrations
of chalcone were obtained in the wavelength range of 200–260
nm at 298 K. The concentration of BSA was kept constant at 5 μM.</p>
</sec>
<sec id="sec4.7"><title>Molecular Docking Studies</title>
<p>The lead drug C01 was assessed
for its binding with the serum protein BSA to analyze its physiological
profile. The three-dimensional (3D) BSA crystal structure was retrieved
from the Protein Data Bank with PDB ID 4OR0. The crystal structure
was analyzed by using the multistep program of the preparation wizard
of the maestro server. The 3D structure was processed, energy-minimized,
and optimized. Also, it was checked if any ligand or any other unwanted
molecules are bound to the structure. Also, the structure was evaluated
for stereochemical parameters through the Ramachandran plot and other
computational avenues, including the Verify 3D, Swiss model structure
assessment suite, and saves server.<sup><xref ref-type="bibr" rid="ref75">75</xref>
−<xref ref-type="bibr" rid="ref77">77</xref>
</sup>
Before molecular docking,
the BSA 3D structure was optimized and prepared. The BSA structure
was prepared to employ the protein preparation wizard of WhatIf server
(<uri xlink:href="https://swift.cmbi.umcn.nl/servers">https://swift.cmbi.umcn.nl/servers</uri>
). Water molecules were also discarded from the 3D structure to analyze
the dry trajectories. Chalcone was drawn using the Chemdraw software
and saved in the desired format (.sdf and.mol) for molecular docking.</p>
<p>Molecular docking is an interactive assessment approach for drugs
with target receptors. We have executed the molecular docking of C01
with the BSA protein using the Autodock tool. Open-screen endeavor
MTiAutodock server was employed to perform molecular docking studies.
The prepared receptor BSA protein and ligand files of C01 were provided.
Autodock performs the docking of ligand file to set off grids with
the target BSA protein, and the scoring calculation on GPU was done
for these grid binding. Autodock outputs 1000 energy conformation
of interaction, out of which the top complex system was considered
and further evaluated.</p>
<p>Moreover, to strengthen our results,
we have redocked the C01 with
BSA using the molecular docking software HEX 8.0. Hex 8.0 works by
the fast Fourier transformations algorithm to give the interacting
energy conformations through the electrostatic potentials and steric
shapes. The resulting docked complex was analyzed to identify the
molecular interaction using the Ligplot, and binding conformations
were analyzed using the chimera molecular modeling suite.<sup><xref ref-type="bibr" rid="ref78">78</xref>
</sup>
</p>
</sec>
<sec id="sec4.8"><title>Molecular Dynamic Simulations Studies</title>
<p>The docked complex
system of BSA–C01 was assessed through the molecular dynamics
simulation. The stability of the complex was analyzed by the complex
dynamics of normal modes of protein using the iMod server.<sup><xref ref-type="bibr" rid="ref79">79</xref>
,<xref ref-type="bibr" rid="ref80">80</xref>
</sup>
This server works by determining the direction of motions and the
range of motion of the docked complex system in terms of B-factors,
deformability, and covariance scores. A minimal deformability plot
will show the stability of the complex with very little fluctuation
by analyzing the drug’s ability to stabilize or deform the
complex rigidity. Besides, Eigen scoring function was calculated,
which signifies the atomic motion composed of rigidity and complexity
of the docked system. It has a direct relation with the energy level
for complex stability and deformation (a low Eigen score leads to
deformation), and the Eigen score of BSA residues is shown in the
covariance matrix unit by independent component analysis approach.</p>
</sec>
<sec id="sec4.9"><title>Bioavailability Absorption Analysis of Drug by Boiled Egg Permeation</title>
<p>For designing and development of potential drugs, it is needed
to assess the bioavailability for pharmacokinetics and gastrointestinal
absorption at different levels. We have assessed the gastrointestinal
absorption and brain penetration capacity through the estimated permeation
method (boiled egg) using the accurate predictive model algorithm.
It works by analyzing the lipophilicity (Log <italic>P</italic>
) and the polar nature of the drug (TPSC) from a large drug dataset
with 93% accuracy.<sup><xref ref-type="bibr" rid="ref81">81</xref>
,<xref ref-type="bibr" rid="ref82">82</xref>
</sup>
</p>
</sec>
<sec id="sec4.10"><title>Pharmacological Analysis
of the Chalcone</title>
<p>The lead compound
C01 was studied for its pharmacokinetic and pharmacodynamic studies
through many computational servers: ACD/I-Lab, pkCSM, SwissADME, and
Molinspiration. Pharmacological parameters were assessed based on
the Lipinski rule of five and drug-likeness.</p>
</sec>
</sec>
</body>
<back><notes id="notes-1" notes-type="si"><title>Supporting Information Available</title>
<p>The Supporting Information
is available free of charge at <ext-link ext-link-type="uri" xlink:href="https://pubs.acs.org/doi/10.1021/acsomega.9b03479?goto=supporting-info">https://pubs.acs.org/doi/10.1021/acsomega.9b03479</ext-link>
.<list id="silist" list-type="simple"><list-item><p>Claisen–Schmidt
condensation reaction for chalcone
synthesis (Scheme S1); cell parameters: bond lengths and bond angles
of C<sub>16</sub>
H<sub>12</sub>
Cl<sub>2</sub>
O<sub>3</sub>
(Table
S1); structural estimation of bovine serum albumin (Figure S1); local
stability estimation of the drug–BSA complex and eigenvalue
calculation (Figure S2); <sup>1</sup>
H NMR spectra of C01 (Figure
S3); <sup>13</sup>
C NMR spectra of C01 (Figure S4); HRMS of C01 (Figure
S5); FT-IR spectra of C01 (Figure S6); UV–vis absorption spectra
of C01 (Figure S7); and SEM images of chalcone with and without modification
(Figure S8) (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b03479/suppl_file/ao9b03479_si_001.pdf">PDF</ext-link>
)</p>
</list-item>
</list>
</p>
</notes>
<sec sec-type="supplementary-material"><title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="sifile1"><media xlink:href="ao9b03479_si_001.pdf"><caption><p>ao9b03479_si_001.pdf</p>
</caption>
</media>
</supplementary-material>
</sec>
<notes notes-type="" id="notes-2"><title>Author Contributions</title>
<p>N.S., N.K.,
D.S., and R.C. designed and performed the experimental studies. N.S.
and N.K. carried out the in silico experiments. The manuscript was
written by N.S., G.R., A.S., V.T., and S.K.D.</p>
</notes>
<notes notes-type="COI-statement" id="NOTES-d7e2012-autogenerated"><p>The authors declare
no
competing financial interest.</p>
</notes>
<ack><title>Acknowledgments</title>
<p>The
authors are grateful to DST-SERB (EEQ/2016/000489) for
providing financial assistance to Prof. Ramesh Chandra. They are also
grateful to Council of Scientific and Industrial Research (CSIR) for
necessary funds. They would like to acknowledge University of Delhi
for providing support and necessary facilities to carry out the research
work. Nidhi Singh is grateful to CSIR-SRF for providing the fellowship.</p>
</ack>
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