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Molecular Simulation
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Theoretical studies on interaction of anticancer drugs

(dacarbazine, procarbazine and triethylenemelamine)
with normal (AT and GC) and mismatch (GG, CC, AA
and TT) base pairs
ab a b a a
R. Shankar , R. Radhika , D. Thangamani , L. Senthil Kumar & P. Kolandaivel
a
Department of Physics, Bharathiar University, Coimbatore 641 046, India
b
Defence Research & Development Organization, Bharathiar University Center for Life
Sciences, Coimbatore 641 046, India
Published online: 27 May 2014.

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To cite this article: R. Shankar, R. Radhika, D. Thangamani, L. Senthil Kumar & P. Kolandaivel (2014): Theoretical studies on
interaction of anticancer drugs (dacarbazine, procarbazine and triethylenemelamine) with normal (AT and GC) and mismatch
(GG, CC, AA and TT) base pairs, Molecular Simulation, DOI: 10.1080/08927022.2014.913098

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 Molecular Simulation, 2014
http://dx.doi.org/10.1080/08927022.2014.913098

Theoretical studies on interaction of anticancer drugs (dacarbazine, procarbazine and

triethylenemelamine) with normal (AT and GC) and mismatch (GG, CC, AA and TT) base pairs
R. Shankara,b*, R. Radhikaa, D. Thangamanib, L. Senthil Kumara and P. Kolandaivela*
a
Department of Physics, Bharathiar University, Coimbatore 641 046, India; bDefence Research & Development Organization,
Bharathiar University Center for Life Sciences, Coimbatore 641 046, India
(Received 19 June 2013; final version received 4 April 2014)

This study is an attempt to gain a better understanding of the physicochemical interaction between novel anticancer drugs
and DNA bases. We have employed quantum chemical tools to explore the interaction of a few anticancer drugs [namely
procarbazine (PR), dacarbazine (DC) and triethylenemelamine (TR)] with isolated normal (GC and AT) and mismatch (AA,
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CC, GG and TT) base pairs. The molecular geometries, electronic structural stability, vibrational energies, chemical
reactivity and other electronic properties were studied using MP2/6-311 þ G**, B3LYP/6-311 þ G** and M05-2X/6-
311 þ G** methods. The optimised geometries of the usual and mismatch base pairs are almost planar whereas the
geometries of drug-interacting complexes deviate from planarity. The presence of steric hindrance and p-bond overlaps
between CZC bonds in the complexes has distorted the planarity of the four- and five-member rings in the base pairs.
Among the three drugs chosen, DC and PR bond well with normal and mismatch base pairs with large interaction energy.
The electron density (ED) difference maps of the most stable GG – DC, GG – PR and GG –TR drug-interacting complexes
show the information about sharing of ED and gain or loss of ED within the interacting molecules. The stabilisation energy
of the charge transfer interaction between the relevant donor – acceptor orbital of GG – DC and GC – DC complexes has been
found to be around 16 kcal/mol and GG – PR and GC – PR complexes has been found to be around 12 kcal/mol. But, for the
GG – TR and GC – TR complexes, the stabilisation energy is found to be less than 6 kcal/mol. Moreover, the topological
analysis of hydrogen bond network of DC and PR drug-interacting complexes have high electron and Laplacian density with
structural stability at the bond critical points (BCPs), while compared TR drug-interacting complexes by atoms in molecules
and natural bond orbital analysis. Finally, we may conclude that the drugs DC and PR are highly efficient drugs to target
normal and mismatch base pair for control and inhibition of DNA replication.
Keywords: procarbazine; dacarbazine; triethylenemelamine; M05-2X; antitumour drugs

1. Introduction formation of complex between drugs and DNA affects the

The studies on binding mechanism of some small
molecules with DNA have been the subject of extensive
research and identified as one of the key topic during the
past few decades. Especially in the recent years, the
interaction between different kinds of anticancer drugs and
DNA has received great interest, notably in the
chemotherapeutic inhibition of DNA replication in rapidly
growing cancer cells. Moreover, it is of great help in
understanding the structural properties of DNA, the
mutation of genes, the origin of some diseases and also the
reaction mechanism of antitumour and antiviral drugs.
Hence to design new, more efficient DNA-targeted drugs
to deal with genetic diseases. In addition, the analytical
results carry information for molecular recognition in
DNA hybridisation and for sensing of bioactive species,
such as anticancer drugs.[1,2] Many studies suggest that
DNA is the primary intracellular target of antitumour
drugs, because the interaction between drug molecules and
DNA can cause DNA damage in cancer cells, blocking the
division of cancer cells and resulting in cell death.[3] The
conformation of the DNA backbone, due to which the
thermodynamic stability and the functional properties of
DNA tend to change. Understanding how complexation
affects both the structural and mechanical properties of
DNA is an important step towards elucidating the
functional mechanism of binding agents and may also
provide information towards more rational drug design.
[1,4,5] For the past few decades, much attention was paid
to the numerous compounds developed as potential
candidates for anticancer drugs, but only a handful of
them have become effective clinical drugs.[6 – 12] The
need to develop new drugs in order to effectively treat
various forms of cancer is widely recognised. The
development of new drugs requires better understanding
of the underlying mechanism of the drug action at the
cellular and molecular levels. The concept of drug –DNA
interaction was first formulated by Lerman [13] in 1961; it
has become widely recognised that many compounds of
pharmacological interest, including anticancer drugs and
antibiotics, correlate their biological and therapeutic
activities with the ability to interact with DNA.

*Corresponding authors. Email: shankardft@gmail.com; ponkvel@hotmail.com

q 2014 Taylor & Francis
 2 R. Shankar et al.
The detection and targeting of single base pair
mismatches in DNA will provide an avenue for the
rational development of new diagnostics and chemother-
apeutics. Despite the considerable amount of efforts made
to understand the mechanism of the procarbazine (PR),
[14 – 19] dacarbazine (DC) [20 – 26] and triethylenemela-
mine (TR),[27 – 29] only a little was known regarding the
structure and interactions between drug – DNA base pair
molecules. Hence, theoretical studies on drug binding with
a single usual and mismatch base pairs are very important
to understand the activity of drug molecules in DNA. Very
recently, Kothandapani et al. [30] have studied the cis-
diamminedichloroplatinum, cisplatin and methoxyamine
as an anticancer drug to target mismatch base pair for the
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control and inhibition of DNA replication. Sponer et al.
[31] interacted metal ions with unusual base pairs and
studied the influence of metal on the neighbouring
hydrogen bonds in the usual and mismatch base pairs.
Deepa et al. [32,33] have reported 5-fluorouracil and
hydroxyurea as anticancer drugs that interact with usual
and mismatch base pairs to control the replication using
quantum chemical calculations. In this investigation, we
have studied the interaction of already clinically
established anticancer drugs such as DC, PR and TR
with normal and mismatch base pairs that can kill the
cancer cells with minimal side effects and toxicity.
PR, a clinically established inhibitor of DNA, plays an
important role in treating lung tumour, brain tumour,
malignant melanoma and skin tumour [14 –16] with low
toxicity. It was first synthesised as a monoamine-oxidase
inhibitor, but was later developed as an anticancer agent.
[17] Most of the anticancer drugs contain an N-methyl
group which is essential for their activity, but do not
contain a chloroethyl group which is present in nitrogen
mustard-type alkylating drugs.[18] DC [5-(3,3-dimethyl-
triazeno) imidazole-4carboxamide] is an imidazole-
carboxamide derivative, structurally related to purines.
It was synthesised for the first time in 1959 at the Southern
Research Institute of Birmingham, Alabama.[19] In 1970,
after several in vivo and in vitro studies, it was approved in
the USA and in France for the treatment of metastatic
melanoma, soft tissues sarcoma, malignant tumours,
Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.[19]
DC is a member of the class of alkylating agents, which
destroy cancer cells by adding an alkyl group (CnH2nþ1) to
its DNA. Now, it is considered to be the reference
compound for the management of advanced melanoma
and soft tissue sarcoma.[20] Marchesi et al. [21] have
reported that DC is one of the alkylating agents that belong
to the family of triazene compound and the active site of
these compounds is represented by the triazenyl group, i.e.
three adjacent nitrogen atoms are responsible for the
chemical, physical and antitumour properties of the
molecule. Engert et al. have [22] reported that DC is
often used in combination with other chemotherapeutic
agents against advanced stage Hodgkin’s disease, and also
used against advanced malignant melanoma.[23] In fact,
DC is the only chemotherapeutic agent approved by the
US Food and Drug Administration for metastatic
melanoma.[24] Kumar et al. [25] have investigated the
effects of DC on testicular function in mice and also
analysed the genotoxic and cytotoxic germ cell damage
more efficiently. Sanada et al. [26] have reported that, after
metabolic activation, DC attacks the DNA and alkylates
the bases, thereby preventing the multiplication of rapidly
growing tumour cells. Romagna and Schneider [27]
confirms that PR and TR are highly effective drugs for the
bone marrow with low toxicity. TR is nitrogen mustard
that acts as an alkylating agent and is known to be a
primary carcinogen that interacts with DNA to form
adducts.[28,29] This compound has been used as an anti-
neoplastic drug and as an experimental carcinogen causing
ovarian, thymic, lung and skin cancers.[28,29] It is a
powerful clastogen and has been reported to produce
heritable translocations, point mutations and reproductive
effects in rodents and other organisms.[28] TR is a
clinically well-established drug with low toxicity.
In this study, we employ quantum chemical tools to
explore the interaction of isolated normal and mismatch
base pairs of DNA with few anticancer drugs (DC, PR and
TR) and the corresponding reaction scheme of the drug –
DNA are shown in Figure 1. During the interaction, the
change of molecular geometries, structural stability,
energy properties and electrostatic potential involved in
the isolated normal base pairs (GC and AT) and mismatch
base pairs (AA, CC, GG and TT) and also (PR, DC and TR
with above-mentioned base pairs) drug – DNA complexes
have been studied. The influences of drugs on hydrogen-
bonding network of nucleobases have been analysed
through interaction energy, three-body analyses and ED
analyses using atoms in molecules (AIM) theory and
natural bond orbital (NBO) method.
2. Computational methods
The geometry of normal base pairs, selected mismatch
base pairs and drug –DNA complex have been optimised
using B3LYP/6-311 þ G** basis set with Becke’s three-
parameter exact-exchange functional combined with
gradient-corrected correlation functional of Lee, Yang
and Parr represented as B3LYP [34] of density functional
theory (DFT). The vibrational frequency calculations have
been performed at the same level of theory, and it has been
confirmed that the structures are on real minima without
imaginary frequencies. In addition, in order to achieve a
more rigorous energy comparison between the complexes,
single-point energy calculation has been performed at
second-order Møller– Plesset perturbation theory (MP2/6-
311 þ G**) of ab initio and M05-2X/6-311 þ G**

Base Pairs Drug Molecules
GC
Dacarbazine(DC),
AT
AA
Procarbazine(PR)
CC
GG
Triethylenemelamine(TR)
TT
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Figure 1. Reaction scheme of the drug– DNA complexes (DC, PR and TR with AA, AT, CC, GC, GG and TT).
functional of DFT methods. Recently, a number of new
density functionals have been developed to understand a
variety of problems pertaining to chemical and biological
systems. It is found from the study of Zhao and Truhlar
that the new hybrid meta-exchange correlation functional
(M05-2X) is one of the best functionals suitable for
probing the H-bonding and non-covalent interactions
compared with the other functionals.[35] The interaction
energies for the optimised base pairs and drug-interacting
complexes have been corrected for the basis set super-
position error (BSSE), through the counterpoise methods
of Boys and Bernardi [36]. The many-body analysis
[37,38] was performed for these drug-interacting com-
plexes, by partitioning the interaction energy into two- and
three-body analysis,
DETotal ¼ EðABCÞ 2 ½EðAÞ þ EðBÞ þ EðCÞ

D E ðABCÞ ¼ DETotal 2 ½D2 EðABÞ þ D2 E ðACÞ þ D2 E ðBCÞ
;
3
D2 E ðABÞ ¼ EAB 2 ½EðAÞ þ EðBÞ

where E(ABC) is the total energy of drug-interacting base
pairs and EA, EB and EC are the total energies of single
base pair or drug and EAB is the total energy of any two-
interacting molecules (base pairs or base pairs with a
drug). Note that while calculating many-body interaction
energies, the BSSE was corrected.
To confirm the presence of hydrogen bonding and
to obtain information about an charge transfer, a
topological analysis was carried out to calculate the
charge density r(r) and its second-order derivative
Laplacian of charge density 72r(r) for bonds using
Bader’s AIM theory.[36 –41] The wave function files were
generated from the Gaussian output files at the B3LYP/6-
311 þ G** level of theory to perform AIM calculations,
and it was carried out using MORPHY 98 program
Package.[42] In order to obtain more specific information
Molecular Simulation 3
Drug-DNA Complexes
GC DC,PR&TR
AT DC,PR&TR
AA DC,PR&TR
CC DC,PR&TR
GG DC,PR&TR
TT DC,PR&TR
on hydrogen bonding, the NBO analysis was also
performed to examine charge transfer between the
interacting orbitals of isolated and drug-interacting
complexes at B3LYP/6-311 þ G** level of theory. The
sharing of ED between the interacting molecules was
shown through the ED difference map. All the calculations
were performed using the Gaussian 09W program.[43]
3. Results and discussion
The geometry of isolated two normal DNA base pairs (GC
and AT) and four mismatch DNA base pairs (AA, CC, GG
and TT) and isolated DC, PR and TR anticancer drug
molecules were optimised at B3LYP/6-311 þ G** level
of theory, which are presented in Figures 2 and 3 along
with their H-bonding distances. In addition, the above-
mentioned most stable normal and mismatch DNA base
pairs interaction with DC, PR and TR of anticancer drug –
DNA complexes were optimised at B3LYP/6-311 þ G**
level of theory, as shown in Figure 4 and Figure S1, where
the values of hydrogen bond lengths are mentioned in Å.
For the construction of the tri-molecular drug –DNA
complexes, in the first step, the initial geometry of the
normal and mismatch isolated GC, AT, GG, CC, AA and
TT base pairs were extracted from the crystallographic
data of Protein Data Bank.[44,45] In the second step, the
above-mentioned extract base pairs were optimised at
B3LYP/6-311 þ G** level of the DFT method. The
vibrational frequency calculations were also performed at
the same level of theory and it confirmed that the
optimised base pairs are real minima without imaginary
frequencies. Then, the optimised electronic geometry and
structural parameters of the above-mentioned isolated base
pairs were compared with previously available literature
[32,33] and the corresponding structural deformations
were found to be less than 1%. Similarly, the drug
molecules DC, PR and TR were also to be optimised at the
 4 R. Shankar et al.
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Figure 2. Optimised structures of usual base pairs (GC and AT) and mismatch base pairs (AA, CC, GG and TT) at B3LYP/6-311 þ G**
level of theory.
same level theory. For the third step, optimised DC, PR
and TR drug molecules with optimised isolated base pairs
interacted with three different initial geometries at
B3LYP/6-311 þ G** level of theory and the vibrational
frequency calculations were also performed at same level
of theory, and it confirmed the true minima. The final step
of the tri-molecular drug – DNA complexes is to find the
most stable drug –DNA complexes. In general, for every
reaction or interaction of two or more molecules, there are
certainly many potential pathways, and to find the most
feasible pathway is one of the challenging tasks. In this
study, the above-mentioned drug molecules interact with
DNA bases in three different initial geometries (C1, C2
and C3). Due to the above-mentioned interactions (C1, C2
and C3), finally 54 drug – DNA complexes were obtained.
Among these 54 different complex structures, we selected
least energy complex structures; and (DC, PR, TR drugs
with GC, AT, GG, CC, AA and TT base pairs) – C1 was
found to be the most stable complex. These drug –DNA –
C1 complexes were subjected to further interaction and
structural studies. The geometry of all isolated normal and
mismatch base pairs were found to be planar [46,32,33]
and during the interaction of anticancer drugs molecules
(DC, PC and TR) with the DNA base pairs, the entire

hydrogen bond networks between the base pairs were
almost completely cleaved and a new hydrogen bond
network was formed with drug molecules. Among all the
drug – DNA complexes, the DC-interacted base pairs were
found to strongly hydrogen bonded, which makes them
more stabilised.
The binding of the base pairs with drug molecules leads
to a conformational changes in DNA at the active site of
carbonyl, amine and amide groups of the base pairs.
Moreover, the geometry of the drug-interacted complexes
are observed to be slightly deviated from the planarity
which leads to change in the bond lengths of the base pairs
from 0.01 to 1.00 Å and bond angles from 1 to 108
depending upon the interaction of drug molecules. The
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p-bond overlapping between CZC bonds are highly
delocalised, which leads to planarity of the four- and five-
member rings of the base pairs. Among the DNA base pairs
we chose, the GG and GC complexes were found to have
high value of structural deformation. The above-mentioned
structural deformation in the geometry leads to stabilisation
Figure 3. Optimised structures of isolated DC, PR and TR anticancer drug molecules at B3LYP/6-311 þ G** level of theory.
Molecular Simulation 5
of the DNA base pairs and control of replication and
transcription processes of DNA in cancer cells.[47 –50]
3.1 Interaction energy
The interaction energy and many-body interaction
energies were calculated after correcting the BSSE for
isolated and drug-interacted complexes of both normal and
mismatch base pairs using B3LYP/6-311 þ G** level of
theory (listed in Table 1). In order to achieve a more
rigorous energy comparison between the complexes, the
above-mentioned energies calculated using second-order
MP2 perturbation theory as well as M05-2X functional of
DFT methods and the corresponding results are presented
in Table 1. Among the isolated normal base pairs, GC base
pairs had larger values of interaction energy (Diso) than the
AT base pairs with corresponding energy variations of
2 14.83, 2 15.66 and 2 14.11 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively. These energy
variations may be due to the presence of three strong
 6 R. Shankar et al.
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Figure 3. (Continued)

Figure 4. The optimised structures of the most stable drug – DNA complexes (DC, PR, TR with GC, GG) at B3LYP/6-311 þ G** level
of theory.
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Figure 4. (Continued).
Molecular Simulation
7
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Figure 4. (Continued).
R. Shankar et al.

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Figure 4. (Continued).
hydrogen bond networks (1.789, 1.936 and 1.920 Å) that
occur between G and C base pair, while only a pair of
hydrogen bonds (1.926 and 1.869 Å) tend to stabilise the
AT base pair. From the obtained results, hydrogen bonds
play a vital role in stabilising the normal DNA base pairs
and also present theoretical interaction energy values quite
comparable with the previous results.[32,33]
Among the isolated mismatch base pairs, GG base
pairs had larger interaction energy, with the values of
2 30.16, 2 33.44 and 2 30.09 kcal/mol, while TT base
pairs had lesser interaction energy values of 2 10.85,
2 12.77 and 2 9.99 kcal/mol at B3LYP, M05-2X and MP2
levels of theory, respectively. The interaction energy
variation between GG and TT base pairs were found to be
2 19.31, 2 20.67 and 2 20.01 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively, and these
energy variations reflect the influence of two and three
strong hydrogen bonds in these base pairs. From the
observed results, the isolated mismatch base pairs GG and
CC had maximum values of interaction energies (around
Molecular Simulation 9
31 kcal/mol), and AA and TT base pairs had minimum
values of interaction energies (around 13 kcal/mol) at
B3LYP, M05-2X and MP2 levels of theory, respectively.
Moreover, the interaction energy difference between
normal GC and AT base pairs was found to be around
30 kcal/mol at B3LYP, M05-2X and MP2 levels of
theories.
Moreover, the number of strong hydrogen bonds and
stability of the hydrogen bonds is one of the factors
to stabilise the above-mentioned base pairs. The order
of interaction energy of isolated normal and mismatch base
pairs was found to be GG . CC . GC . AT . AA .
TT. The interaction energy values calculated using M05-2X
method is slightly overestimated compared with that of the
B3LYP and MP2 levels of theory.[51] The two-body
interaction energies calculated for isolated normal and
mismatch base pairs (Diso) were found to be higher than that
of the same base pairs in drug-interacting complexes (DETot).
The (DETot) interaction between the base pairs of the
complexes were found to be decreased, which leads to altered
 10 R. Shankar et al.
stability of the complexes. This may be due to the influence of
the drug molecules. Among the drug-interacted complexes,
the GG and GC with drug molecules had larger values of
interaction energy with huge structural stability, whereas the
AT base pairs with drug molecules had lower values of
interaction energy and stability at B3LYP, M05-2X and
MP2 levels of theory, respectively. The DETot interaction
energy of GG–DC complexes were found to have larger
values of interaction energies of 242.40, 249.47 and
245.23 kcal/ mol, while the AT–TR complex was found to
have lower values of interaction energies of 24.49, 29.26
and 28.99 kcal/ mol at B3LYP, M05-2X and MP2 levels of
theory, respectively.
For the DC complexes, the interaction energy orders
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were found to be GG – DC . GC – DC . CC –
DC . AA – DC . TT – DC . AT –DC at B3LYP, M05-
2X and MP2 levels of theory. The two-body interaction
energy (D2E) corresponding to guanine base pairs (GG)
and guanine –cytosine base pair (GC) with drug-interacted
DC complexes were found to be maximum. This may be
due to the contribution of G1 – DC and G2 – DC
interactions in GG – drug complex and also for G1 –DC
and C2 – DC interactions in GC –drug complex, respect-
ively, whose values of interaction energy were larger while
compared with all other two-body interactions of DC
complexes. Moreover, for the most stable GC – DC and
GG –DC drug-interacted complexes, the GC and GG base
pairs serve as a proton donor and proton acceptor with the
DC drug molecule. The corresponding two-body inter-
action energies of G1–DC, G2–DC and G1–DC, C2–DC
were found to be (218.91, 222.03 and 2 20.03 kcal/mol),
(28.77, 2 11.65 and 210.20 kcal/mol) and (2 17.95,
2 20.90 and 2 18.59 kcal/mol), (2 9.47, 2 12.32 and
210.78 kcal/mol) at B3LYP, M05-2X and MP2 levels of
theory, respectively. Three-body interaction energies (D3E)
of the GG–DC complexes were found to be 28.1, 26.06
and 2 6.02 kcal/mol and of the GG–DC complex were
found to be 25.55, 25.81 and 24.66 kcal/mol at B3LYP,
M05-2X and MP2 levels of theory, respectively. These high
values of D2E and D3E interaction energies make the GG–
DC and GC–DC complexes most stable.
Notably, among the GG – DC and GC –DC complexes,
the GG base pairs with DC complexes were found to be the
most stable complexes with larger two-body (D2E) and
three-body (D3E) interaction energies. In the case of AT
base pairs with drug molecules (AT– DC complexes), the
D2E interaction energies were found to be lower with
values of 2 4.01, 2 2.43 and 2 3.01 kcal/mol at B3LYP,
M05-2X and MP2 levels of theory, and also the D3E
interaction energies were found to have positive values of
4.15, 1.33 and 1.25 kcal/mol at B3LYP, M05-2X and MP2
levels of theory. These results indicated weak attraction in
the AT– DC complex. In the case of PR complexes, the
total interaction energy for GG – PR complex was found to
be 2 35.54, 2 41.44 and 2 40.01 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively. The
corresponding two- and three-body interaction energies
were calculated to be 2 8.34, 2 9.20 and 2 8.74 kcal/mol
and 2 7.68, 2 9.51 and 2 5.74 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively. The presence of
negative values of D2E and D3E interaction energies
confirms the strong attractive interaction in the GG –PR
complexes. For the GC – PR complex, the interaction
energy of DE was found to be 2 34.81, 2 40.00 and
2 37.30 kcal/mol and the corresponding D2E and D3E
values were found to be 2 8.3, 2 9.20 and 2 8.32 kcal/mol
and 2 7.58, 2 7.40 and 2 4.53 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively. The interaction
energy order of the base pair with drug (PR)-interacting
complexes was found to be GG –PR . GC –PR . AA –
PR . CC – PR . TT – PR . AT –PR. The least stable PR-
interacting complex was AT –PR, with interaction energies
of 2 13.59, 2 18.42 and 2 17.77 kcal/mol and the
corresponding D2E and D3E were found to be 2 2.12,
2 3.16 and 2 2.84 kcal/mol and 0.15, 0.09 and 0.26 kcal/
mol at B3LYP, M05-2X and MP2 levels of theory,
respectively. Among the TR complexes, GG –TR mis-
match base pair was found to have the larger interaction
energies of 2 28.11, 2 34.52 and 2 36.86 kcal/mol, and
the corresponding two- and three-body interaction
energies were found to be 2 9.89, 2 11.00 and 2 12.28
and 2 1.79, 2 1.57 and 2 0.73 kcal/mol at B3LYP, M05-
2X and MP2 levels of theory, respectively. The order of the
stability of TR complexes was found to be GG –
TR . GC – TR . CC – TR . AA – TR . TT –TR . AT –
TR. The AT – TR mismatch base pair complex had lower
values of interaction energy and positive values of three-
body interaction energies of 0.41, 0.38, 0.37 kcal/mol at
B3LYP, M05-2X and MP2 levels of theory, respectively,
confirming the minimum stability of the complexes.
From the obtained results, the drugs DC, PR and TR
bonded well with the normal and mismatch base pairs, but
the order of corresponding interaction energies were found
to be different. Among the three drugs, except few cases,
the DC and PR drug molecules bonded well with normal
and mismatch base pairs with higher values of interaction
energy and stability. This may be due to the presence of
more number of amino and amine groups which have
resulted in strong hydrogen-bonded interactions and led to
more stability. The stability of the hydrogen-bonded
complexes depends not only on the number of hydrogen
bonds, but also its strength and mutual orientation of
molecular dipole moment.[46,33,52]
The frontier molecular orbital (MO) energies of the
isolated DC, PR and TR drugs were calculated at
B3LYP/6-311 þ G** level of theory, and the correspond-
ing MO energies are listed in Table 2. From the obtained
MO energies, all the drugs were found to be good electron
acceptors with minimum (lowest unoccupied MOs)
LUMO energy. The LUMO value of the DC drug
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Table 1. Interaction energies (in kcal/mol) of DC-, PR- and TR-interacting complexes and their respective base pairs.
Interaction energies in kcal/mol Interaction energies in kcal/mol Interaction energies in kcal/mol

GC – DC GC – PR GC – TR

Base pair B3LYP M05-2x MP2 Base pair B3LYP M05-2x MP2 Base pair B3LYP M05-2x MP2
2 2 2
D Eiso 2 28.03 2 31.01 2 27.99 D Eiso 2 28.03 2 31.01 2 27.99 D Eiso 2 28.03 2 31.01 2 27.99
DETot 2 41.52 2 48.29 2 43.24 DETot 2 34.81 2 40.00 2 37.30 DETot 2 23.54 2 33.02 2 29.59
(CþDC)
D2E com 2 9.47 2 12.32 2 10.78 (GþPR)
D2E com 2 12.12 2 15.15 2 13.62 (CþTR)
D2E com 2 9.67 2 14.75 2 13.24
(GþDC)
D2E com 2 17.95 2 20.90 2 18.59 (CþPR)
D2E com 2 6.81 2 8.25 2 10.83 (GþTR)
D2E com 2 10.36 2 15.61 2 14.74
2 2 2
D EGC 2 8.55 2 9.26 2 9.21 D ECC 2 8.30 2 9.20 28.32 D EGC 2 1.76 2 1.82 2 1.28
3 3 3
DE 2 5.55 2 5.81 2 4.66 DE 2 7.58 2 7.4 24.53 DE 2 1.75 2 0.84 2 0.33

AT – DC AT – PR AT – TR
2 2 2
D Eiso 2 13.20 2 15.35 2 13.88 D Eiso 2 13.20 2 15.35 2 13.88 D Eiso 2 13.20 2 15.35 2 13.88
DETot 2 19.80 2 23.98 2 22.45 DETot 2 13.59 2 18.42 2 17.77 DETot 2 4.49 2 9.26 2 8.99
(AþDC)
D2E com 2 7.23 2 8.52 2 8.21 (A1þPR)
D2E com 2 6.85 2 8.97 28.26 (AþTR)
D2E com 2 0.43 2 2.04 2 1.82
(TþDC)
D2E com 2 12.71 2 14.36 2 12.48 (A2þPR)
D2E com 2 4.77 2 6.38 26.41 (TþTR)
D2E com 2 5.40 2 7.83 2 7.83
D2EAT 2 4.01 2 2.43 2 3.01 D2EAA 2 2.12 2 3.16 22.84 D2EAT 2 1.07 2 1.77 2 1.71
D3E 4.15 1.33 1.25 D3E 0.15 0.09 20.26 D3E 0.41 0.38 0.37

GG – DC GG – PR GG – TR

D2Eiso 2 30.16 2 33.44 2 30.09 D2Eiso 2 30.16 2 33.44 2 30.09 D2Eiso 2 30.16 2 33.44 2 30.09
DETot 2 42.40 2 49.47 2 45.23 DETot 2 35.54 2 41.44 2 40.01 DETot 2 28.11 2 34.52 2 36.86
(G1þDC)
D2E com 2 8.77 2 11.65 2 10.20 (T1þPR)
D2E com 2 6.33 2 7.58 2 10.17 (G1þTR)
D2E com 2 2.64 2 5.19 2 5.76
(G2þDC)
D2E com 2 18.91 2 22.03 2 20.12 (T2þPR)
D2E com 2 13.19 2 15.15 2 15.36 (G2þTR)
D2E com 2 13.79 2 16.76 2 18.09
D2EGG 2 6.62 2 9.73 2 8.89 D2ETT 2 8.34 2 9.20 28.74 D2EGC 2 9.89 2 11.00 2 12.28
D3E 2 8.1 2 6.06 2 6.02 D3E 2 7.68 2 9.51 25.74 D3E 2 1.79 2 1.57 2 0.73

CC – DC CC – PR CC – TR

D2Eiso 2 28.10 2 31.11 2 28.08 D2Eiso 2 28.10 2 31.11 2 28.08 D2Eiso 2 28.10 2 31.11 2 28.08
DETot 2 29.80 2 32.63 2 28.95 DETot 2 25.98 2 34.31 2 31.16 DETot 2 18.34 2 27.17 2 22.82
(G1þDC)
D2E com 2 8.12 2 9.34 2 8.33 (C1þPR)
D2E com 2 4.93 2 5.23 26.18 (C1þTR)
D2E com 2 1.35 2 4.06 2 4.09
(G2þDC)
D2E com 2 13.76 2 15.79 2 13.92 (C2þPR)
D2E com 2 10.46 2 15.02 2 13.53 (C2þTR)
D2E com 2 3.09 2 6.01 2 5.28
2 2 2
D ECC 2 8.16 2 5.68 2 5.83 D ECC 2 9.32 2 11.47 29.99 D ECC 2 9.90 2 14.33 2 12.28
3 3 3
DE 0.24 0.18 2 0.87 DE 2 1.27 2 2.59 24.74 DE 2 4.00 2 2.77 2 1.17

AA – DC AA – PR AA – TR
2 2 2
D Eiso 2 11.51 2 12.85 2 11.31 D Eiso 2 11.51 2 12.85 2 11.31 D Eiso 2 11.51 2 12.85 2 11.31
DETot 2 22.47 2 26.20 2 22.45 DETot 2 34.39 2 37.92 2 35.63 DETot 2 7.14 2 10.51 2 10.99
(G1þDC)
D2E com 2 6.90 2 7.92 2 7.38 (A1þPR)
D2E com 2 11.31 2 12.23 2 11.35 (A1þTR)
D2E com 2 5.17 2 8.05 2 7.87
(G2þDC)
D2E com 2 12.79 2 14.28 2 12.87 (A2þPR)
D2E com 2 5.35 2 5.85 28.11 (A2þTR)
D2E com 2 1.13 2 0.11 2 1.09
2 2 2
D EAA 2 1.29 2 3.76 2 1.03 D EAA 2 6.75 2 8.54 25.07 D EAA 2 1.11 2 2.60 2 2.40
3 3 3
DE 2 1.49 2 0.24 2 1.17 DE 2 0.98 2 1.3 22.1 DE 0.27 0.25 0.37

TT – DC TT– PR TT – TR
2 2 2
D Eiso 2 10.85 2 12.77 2 9.99 D Eiso 2 10.85 2 12.77 29.99 D Eiso 2 10.85 2 12.77 2 9.99
DETot 2 22.05 2 27.38 2 24.94 DETot 2 15.22 2 23.16 2 22.40 DETot 2 5.38 2 10.01 2 9.51
(G1þDC)
D2E com 2 8.77 2 11.76 2 10.69 (T1þPR)
D2E com 2 5.21 2 8.32 27.74 (T1þTR)
D2E com 2 0.83 2 2.40 2 2.23
(G2þDC)
D2E com 2 5.03 2 6.05 2 5.44 (T2þPR)
D2E com 2 3.10 2 6.39 26.76 (T2þTR)
D2E com 2 4.69 2 7.74 2 7.27
2 2 2
Molecular Simulation

D ETT 2 6.62 2 7.99 2 7.20 D ETT 2 5.75 2 7.42 26.58 D ETT 2 0.05 2 1.18 2 0.03
3 3 3
DE 2 1.63 2 1.58 2 1.61 DE 2 1.16 2 1.03 21.32 DE 0.19 1.13 0.02

(GþDC) is the interaction energy of guanine base with drug (DC) and similarly for other cases,
Notes: D2Eiso is for isolated base pair, DETot is the total interaction energy of drug-interacting complex, D2E com
11

D2EGG is the interaction energy between guanine bases in the drug-interacting complex and similarly for other cases and D3E is the many-body interaction energy.
 12 R. Shankar et al.

Table 2. The isolated and drug – DNA complexes frontier MOs energies are calculated at B3LYP/6-311 þ G** level of theory.

Drug – DNA complexes

Isolated base pairs DC – DNA complexes PR – DNA complexes TR – DNA complexes
S. no. Base pairs HOMO LUMO HOMO LUMO HOMO LUMO HOMO LUMO
1 GC 26.2 2 0.984 2 5.126 2 1.722 2 5.525 21.267 2 4.96 22.946
2 AT 26.194 2 1.441 2 5.372 2 2.036 2 5.558 21.475 2 5.805 21.602
3 GG 25.873 2 1.745 2 4.979 2 1.723 2 5.493 21.069 2 4.962 22.947
4 CC 25.702 2 1.697 2 5.918 2 1.926 2 5.637 21.351 2 5.231 21.605
5 AA 25.98 2 1.31 2 5.61 2 2.148 2 5.739 21.216 2 5.825 20.867
6 TT 26.814 2 1.48 2 5.538 2 1.512 2 6.319 21.453 2 6.393 21.574
DC* 25.94 2 2.011
PR* 26.377 2 1.227
TR* 26.739 2 0.698
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*Isolated drug molecules.

molecule was found to be 2 2.01 eV; hence, it has more
ability to accept electrons from the DNA base pairs and
tends to stabilise the DC – DNA complexes. In the case of
PR and TR, the LUMO values were found to be 2 1.23 and
2 0.69 eV. These two drugs have low electron-accepting
ability; hence, they interact with DNA base pairs, but not
as strong as the DC – DNA complexes. Previously, Reha
et al. [53] had reported that the drugs are mostly good
electron acceptors and base pairs are evidently good
electron donors, among the base pairs, guanine bases are
effective electron donors. In this study also, the guanine
base pairs (GG and GC) interacted well with drug
molecules.
3.2 Topological analysis
The AIM approach is a useful tool to quantify the non-
covalent interactions such as H-bonding and van der
Waals complex formation.[54 – 57] The topological
analysis of EDs developed by Bader [38,54,55] would be
an intuitive idea to analyse the nature of the bond formed
in the isolated (GC, AT, AA, CC, GG and TT) and drug-
interacted complexes (GC, AT, AA, CC, GG and TT base
pairs with DC, PR and TR drug molecules). From the
isolated base pairs and drug-interacted complexes, the
hydrogen bonds were observed on electronegative atoms
of NZH· · ·O, CZH· · ·O, CZH· · ·N and NZH· · ·N, and the
corresponding bond lengths are presented in Figures 3– 5.
The ED (r), Laplacian of ED (72r) and bond ellipticity (()
at the BCPs were calculated at B3LYP/6-311 þ G** level
of theory for inter- and intra-molecular hydrogen bonds in
all the drug-interacting complexes and the corresponding
results are presented in Tables 3 – 5. All the drug-
interacting complexes were found to be strongly hydrogen
bonded, and the corresponding r and 72r values were
within the range of Popelier criteria.[39,58] It is expected
that the strong bonds are usually associated with higher
electron and Laplacian density and structural stability, as it
is observed for DC and PR drug-interacting complexes.
However, compared with DC and PC drug-interacting
complexes, TR drug-interacting complexes have weak
bonds associated with low electron and Laplacian densities
and structural stability. The ED values calculated at the
BCPs augment the stability order predicted through the
interaction energy and the hydrogen bond distance. The
subsequent correlation between the hydrogen bond length
and ED (r) is inverse, that is, an increase in bond length
corresponds to a decrease in ED. The Laplacian of ED
(72r) and the hydrogen-bond length also reveal an inverse
correlation, analogous to the correlation between ED and
hydrogen bond length. The correlation coefficient for the
ED (r values) and hydrogen bond length of the most stable
GG –DC, GG – PC and GG – TR drug-interacted complex
were found to be 0.972, 0.996 and 0.982, respectively, at
B3LYP/6-311 þ G** level of theory. Similarly, corre-
lation coefficient for the Laplacian of ED (72r) and
hydrogen bond length of the above-mentioned drug-
interacted complexes were found to be 0.963, 0.976 and
0.994 at B3LYP/6-311 þ G** level of theory. In addition,
the correlation coefficient for ED (r) and Laplacian of ED
(72r) values at B3LYP/6-311 þ G** level of theory of the
most stable (GG –DC, GG – PR and GG – TR) drug-
interacted complexes were observed to be 0.959, 0.985
and 0.982, and the correlation graphs are shown in
supplementary Figures S2 – S4.
3.3 NBO analysis
Among the theoretical methods, NBO analysis is a unique
approach to evaluate the delocalisation effects.[59,60] In
this analysis, stabilisation energy E (2) related to the
delocalisation trend of electrons from donor to acceptor
orbitals was calculated via perturbation theory. If the
stabilisation energy E (2) between donor bonding orbital
and the acceptor orbital is large, then there is a strong
interaction between them. For each donor orbital (i) and
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Table 3. Occupation number of the proton donor s*(XZH), acceptor lone pair n(y), the hydrogen bond stabilisation energy E (2), ED, Laplacian of ED and the bond ellipticity
corresponds to hydrogen bonds in (AT, GC, GG, CC, AA, and TT with DC) drug-interacting complexes at B3LYP/6-31 þ G** level of theory.

Bonding Hydrogen-bond length in Å Donor s*(XZH) Acceptor n(y) E (2) in kcal/mol r in a.u. 72r in a.u. 1 in a.u.
AAZDC
N6ZH6b· · ·N1 2.274 0.022 1.900 5.36 0.016 0.045 0.054
N6ZH6b· · ·DO11 1.834 0.050 1.949 6.90 0.033 0.097 0.040
N6ZH6a· · ·DO11 1.951 0.029 1.949 9.52 0.022 0.073 0.013
DN12ZDH12b· · ·N1 2.057 0.046 1.885 13.99 0.024 0.057 0.068
DN12ZDH12a· · ·DN6 2.183 0.026 1.919 5.21 0.018 0.057 0.018
ATZDC
N10ZH6a· · ·DO11 1.931 0.035 1.946 7.86 0.025 0.075 0.028
DN12ZDH12a· · ·O6 1.898 0.063 1.946 14.55 0.034 0.098 0.036
DN12ZDH12b· · ·DN7 1.953 0.045 1.925 15.23 0.030 0.083 0.057
N1ZH1· · ·DO11 1.813 0.062 1.932 14.56 0.028 0.081 0.036
DC10ZDH10a· · ·DN6 2.551 0.011 1.926 1.39 0.019 0.060 0.218
CCZDC
N1ZH1· · ·DO11 2.010 0.035 1.952 5.61 0.076 0.079 0.045
N6ZH6b· · ·DO11 1.856 0.039 1.882 7.91 0.081 0.098 0.103
N1ZH1· · ·N6 2.030 0.048 1.782 14.08 0.023 0.063 0.050
DN12ZDH12a· · ·O2 1.894 0.039 1.960 9.04 0.045 0.090 0.102
DN12ZDH12b· · ·DN7 1.931 0.047 1.923 16.35 0.025 0.109 0.130
DC10ZDH10a· · ·DN6 2.553 0.011 1.925 1.32 0.019 0.060 0.118
GCZDC
N1ZH1· · ·DO11 1.806 0.048 1.906 15.04 0.031 0.113 0.035
N2ZH2a· · ·DO11 2.056 0.032 1.946 3.89 0.021 0.064 0.054
N2ZH2a· · ·DN1 2.464 0.032 1.919 3.31 0.010 0.032 0.143
N8ZH8b· · ·O6 1.957 0.033 1.960 5.44 0.024 0.081 0.022
DN12ZDH12b· · ·N3 2.171 0.034 1.883 8.64 0.018 0.047 0.065
DN12ZDH12a· · ·DN7 1.990 0.041 1.908 13.39 0.027 0.078 0.053
DC9ZDH16· · ·O2 2.215 0.013 1.969 4.34 0.018 0.082 0.043
GGZDC
N2ZH2a· · ·O6 1.886 0.038 1.961 7.89 0.027 0.093 0.016
N1ZH1a· · ·DO11 1.828 0.032 1.947 15.73 0.030 0.109 0.038
N2ZH2a· · ·DO11 2.013 0.036 1.947 4.48 0.023 0.069 0.021
DN12ZDH12a· · ·N1 2.200 0.032 1.881 7.95 0.017 0.045 0.063
DN12ZDH12b· · ·DN7 2.002 0.040 1.920 12.91 0.026 0.076 0.053
DC9ZDH9a· · ·O6 2.216 0.013 1.968 4.34 0.013 0.047 0.046
N2ZH2a· · ·DN1 2.442 0.036 1.919 3.62 0.010 0.033 0.301
TTZDC
N1ZH1· · ·O2 1.933 0.034 1.961 8.46 0.023 0.082 0.033
N3ZH3· · ·O11 1.754 0.059 1.943 9.41 0.035 0.116 0.045
DN12ZDH12a· · ·O2 1.963 0.032 1.965 6.04 0.024 0.072 0.018
DN12ZDH12b· · ·DN1 2.323 0.014 1.921 2.06 0.006 0.025 0.320
Molecular Simulation
13
 14 R. Shankar et al.

Table 4. Occupation number of the proton donor s*(XZH), acceptor lone pair n(y), the hydrogen bond stabilisation energy E (2), ED,
Laplacian of ED and the bond ellipticity corresponds to hydrogen bonds in (AT, GC,GG, CC, AA, and TT with PR) drug-interacting
complexes at B3LYP/6-31 þ G** level of theory.

Hydrogen-bond Donor Acceptor E (2) in

Bonding length in Å s*(XZH) n(y) kcal/mol r in a.u. 72r in a.u. 1 in a.u.
AAZPR
DC1ZDH1· · ·N1 2.569 0.021 1.952 2.79 0.009 0.026 0.042
N6ZH6b· · ·DO11 1.963 0.031 1.963 7.54 0.022 0.072 0.031
N6ZH6a· · ·N1 2.023 0.041 1.886 11.01 0.026 0.064 0.071
N6ZH6b· · ·N7 2.019 0.043 1.914 11.10 0.026 0.063 0.065
ATZPR
N6ZH6a· · ·O4 2.229 0.018 1.973 2.19 0.013 0.045 0.148
N3ZH13· · ·DO11 1.833 0.049 1.918 11.02 0.029 0.096 0.043
N6ZH6b· · ·DO11 2.041 0.023 1.948 4.24 0.019 0.062 0.037
DC13ZDH13· · ·O2 2.543 0.025 1.848 1.45 0.008 0.027 0.009
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CCZPR
N2ZH2a· · ·N3 2.088 0.036 1.880 10.26 0.022 0.057 0.077
N1ZH1· · ·DO11 2.064 0.037 1.955 3.33 0.019 0.055 0.072
N4ZH4a· · ·DO11 1.898 0.041 1.974 9.72 0.027 0.081 0.040
DC1ZDH1· · ·O6 2.460 0.014 1.974 1.35 0.009 0.032 0.074
GCZPR
N1ZH1· · ·DO7 1.920 0.043 1.901 7.66 0.027 0.079 0.061
N4ZH4a· · ·O6 1.885 0.034 1.900 11.63 0.025 0.089 0.023
DN12ZDH12· · ·O2 1.935 0.056 1.965 4.74 0.027 0.073 0.032
GGZPR
N2ZH2a· · ·O6 1.823 0.042 1.851 11.98 0.029 0.100 0.026
N2ZH2b· · ·DO11 1.928 0.031 1.918 4.45 0.026 0.081 0.022
DC3ZDH3· · ·O11 2.385 0.019 1.967 1.01 0.011 0.036 0.090
N1ZH1· · ·DO11 2.098 0.030 1.915 4.34 0.019 0.056 0.069
DN12ZH12· · ·O6 2.062 0.033 1.968 4.01 0.021 0.050 0.072
TTZPR
C7ZH7a· · ·O4 2.413 0.014 1.975 1.35 0.010 0.032 0.035
N3ZH3· · ·O6 1.897 0.042 1.956 11.05 0.025 0.081 0.045
DC13ZDH13· · ·DO11 2.340 0.022 1.959 1.08 0.011 0.036 0.090
N1ZH1· · ·DO11 1.855 0.050 1.959 9.00 0.029 0.088 0.074
DN12ZDH12· · ·O2 2.073 0.031 1.958 4.30 0.020 0.061 0.065

acceptor orbital ( j), the stabilisation energy E (2) is
associated with i ! j delocalisation, given by the
following equation:
F 2 ði; jÞ
E ð2Þ ¼ DEij ¼ qi ; the NBO results of the isolated bare base pair (GG) with the
1j 2 1i
where qi is the ith donor orbital occupancy; 1j and; 1i
are diagonal elements (orbital energies) and F (i,j) is an
off-diagonal element associated with NBO Fock matrix.
[61] The occupation number for the proton donor s*
(XZH) (antibonding occupation values) and for the proton
acceptor lone pairs n(y) and the stabilisation energies E (2)
calculated at B3LYP/6-311 þ G** level of theory and the
corresponding results are summarised in Tables 3– 5.
The stabilisation energies E (2) of the charge transfer
interaction between the relevant donor –acceptor orbital of
GG –DC and GC –DC complexes were observed to be
around 16 kcal/mol, and for the GG – PR and GC – PR
complexes it was found to be around 12 kcal/mol.
However, for the GG –TR and GC – TR complexes, the
stabilisation energies were observed to be less than
6 kcal/mol. Except few cases, these results confirmed the
strong interactions that have been observed for DC and PR
drugs with GG and GC base pairs and asserted for being
more stable than the TR drug complexes. On comparing
most stable drug-interacted base pair (GG – DC, GG –PR
and GG – TR complexes), it was found that the XZH
antibond occupation value and bond length (XZH) of
proton donor were contrast, which leads to the blue shift of
XZH bonds. And also, the bond length (XZH) of the
proton donor and the antibond occupation values were
found to be elongate, which leads to the red shift of XZH
bonds. These results are due to the charge transfer
interaction between the orbitals, where the second lone pair
of either oxygen or nitrogen is found to act as an acceptor
and XZH as a donor in the strong intermolecular charge
transfer interaction in the GG – DC, GG – PR and GG –TR
complexes. To correlate drug-interacted GG – DC, GG –PR
and GG – TR complexes with GG isolated base pair, the
hydrogen bond length and antibonding occupation values
were found to be low which leads to the contraction of
 Molecular Simulation 15

Table 5. Occupation number of the proton donor s*(XZH), acceptor lone pair n(y), the hydrogen bond stabilisation energy E (2), ED,
Laplacian of ED and the bond ellipticity corresponds to hydrogen bonds in (AT, GC,GG, CC, AA, and TT with TR) drug-interacting
complexes at B3LYP/6-31 þ G** level of theory.

Hydrogen-bond Donor Acceptor

Bonding length in Å s*(XZH) n(y) E (2) in kcal/mol r in a.u. 72r in a.u. 1 in a.u.
AAZTR
C2ZH2· · ·N1 2.600 0.028 1.904 1.65 0.007 0.022 0.056
C2ZH2· · ·N1 2.570 0.028 1.903 2.15 0.009 0.029 0.056
N6ZH6a· · ·DN1 2.241 0.023 1.894 5.69 0.016 0.046 0.059
DC9ZDH9b· · ·N7 2.536 0.018 1.927 1.13 0.006 0.021 0.071
ATZTR
C2ZH2· · ·O2 2.528 0.028 1.974 1.25 0.007 0.026 0.024
DC9ZDH9a· · ·N1 2.703 0.018 1.906 1.01 0.008 0.024 0.163
N6ZH6a· · ·DN7 2.065 0.034 1.957 5.16 0.023 0.058 0.045
CCZTR
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DC8ZDH8a· · ·O2 2.441 0.022 1.973 1.02 0.008 0.023 0.070

DC15ZDH15b· · ·O2 2.410 0.025 1.973 2.40 0.010 0.033 0.061
N4ZH4b· · ·O2 2.225 0.019 1.869 3.08 0.013 0.047 0.046
GCZTR
N2ZH2a· · ·DN3 2.335 0.020 1.894 4.78 0.012 0.036 0.057
DC14ZDH14a· · ·DN1 2.292 0.008 1.892 1.23 0.022 0.083 0.061
GGZTR
N2ZH2b· · ·O6 1.808 0.024 1.949 6.90 0.080 0.081 0.053
N1ZH1· · ·DN1 2.026 0.020 1.895 4.78 0.065 0.077 0.069
N2ZH2a· · ·DN7 2.013 0.021 1.899 4.98 0.068 0.077 0.072
TTZTR
DC12ZDH12a· · ·O4 2.449 0.021 1.920 4.10 0.020 0.035 0.063
N3ZH3· · ·DN3 2.392 0.020 1.966 1.12 0.011 0.036 0.090
DC15ZDH15b· · ·O2 2.386 0.019 1.967 2.02 0.020 0.032 0.084

NZH or CZH bonds, which thereby leads to be the most
stable DC and PC complexes. Specifically for the
interaction of GG and GC bases with DC and PR drug
molecules, the single proton acceptor of drug molecules
interacts with two proton donors of the nucleobases, i.e.
(DO11· · ·N1ZH1, DO11· · ·N2ZH2a for GG –DC com-
plexes, DO11· · ·N1ZH1, DO11· · ·N2ZH2a for GC –DC
complexes and DO7· · ·N1ZH1, DO7· · ·N2ZH2a for GG –
PR complexes, DO7· · ·N1ZH1, DO7· · ·N2ZH2a for GG –
DC complexes). Therefore, the occurrence of more number
of bifurcated hydrogen bonds leads to large charge
transfers between base pairs and drugs in the above-
mentioned complexes. In addition to the above-mentioned
interactions, for the GG – DC and GC – DC drug-interacted
complexes, two proton acceptors of the drug molecules
interact with single proton donor of the base pairs through
DN1· · ·N2ZH2, DO11· · ·N2ZH2 for GG –DC complexes
and DN1· · ·N2ZH2, DO11· · ·N2ZH2 for GC – DC com-
plexes. These two sets of bifurcated interactions were also
responsible for the large charge transfer and thereby
stabilising the above-mentioned complexes to be the most
stable. In few cases, the stability of the bifurcated hydrogen
bonds was observed to be less stable than the single
hydrogen bonds; however, the overall structural stability of
the GG – DC and GC –DC complexes were found to be
improved. For the above-mentioned interactions, the
calculated ED at BCPs can be taken as a measure of the
strength of bonding interaction and the corresponding ED
are presented in Tables 3 – 5. Moreover, the presence of
larger number of CZH· · ·O and NZH· · ·O inter- and intra-
molecular strong hydrogen bonded interactions in the DC
and PR complexes is also an important factor which leads
to large charge transfers and improved stability of the
above-mentioned complexes. But in the case of TR
complexes, only weak NZH· · ·N hydrogen bonded
interactions with minimum charge transfer and stabilis-
ation energy were observed. Furthermore, when compared
with the isolated bases, lone pair occupancy values n(y) of
the electron donating site of the drug-interacting
complexes were found to be decreased. Exception has
been found in few cases like, the electron donating
electronegative atoms of the GG and GC complexes have
decreased occupancy values, subsequently this result once
again ascertain the reason for large charge transfer between
drug and the ligands, which has lead the GG and GC
complexes to have higher stability. In addition, Vijayaku-
mar, et al., previously reported that, the increase of ED in
the (s*) anti bonding orbitals of XZH bond leads to
weakening XZH bonds.[62] In the present NBO analysis
of the most stable GG – DC, GG – PR and GG – TR
complexes reveal that, the ED in the (s*) anti bonding
orbitals of the N18ZH31 and N28ZH29 bonds in the
isolated GG base pairs are found to be 0.059 and 0.035.
While at the formation of the GG – DC complex, the above
 16 R. Shankar et al.
mentioned ED is found to be decreased to 0.036 and 0.032
and the corresponding charge variations of the above
N18ZH31 and N28ZH29 bonds in the complex is found to
be 0.023 and 0.003 respectively. Due to the minimal ED
charge variations occurred in the (s*) anti bonding orbitals
of the N18ZH31 and N28ZH29 bonds lead GG –DC
complex to the most stable. Similarly, for the GG – PR
complexes also have minimal amount of ED variations in
the (s*) anti bonding orbitals of the N1ZH1 and N2ZH2b
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Figure 5. (Colour online) The BCP for most interacting drug – DNA complexes (a) GG – DC, (b) GG – PR and (c) GG – TR.
bonds in the complex formation and the corresponding ED
charges are found to be 0.029 and 0.003. But in the case of
GG-TR complexes, the isolated GG base pairs, the EDs in
the (s*) anti bonding orbitals of N1ZH1, N2ZH2a and
N2ZH2b bonds are found to be 0.035, 0.057 and 0.059.
While at the formation of the GG – TR complex, the above
mentioned ED is found to be decreased to 0.024, 0.021 and
0.020 and the corresponding ED charge variations of the
above bonds is found to be 0.012, 0.037 and 0.039
 Molecular Simulation 17
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Figure 6. (Colour online) ED difference maps for most interacting complexes. (a) GG – DC, (b) GG – PR, (c) GG – TR. Here, blue
regions represent the gain in ED as a result of formation of the drug-interacting complex relative to non-interacting nucleobases and drug
molecule; red regions refer to loss of ED. The contour shown is 0.03 e/a.u.3.

respectively, which leads to weakening the above bonds and
GG–TR complex. From the obtained results, confirms that,
more amount of ED charge occurred in the (s*) anti bonding
orbitals of NZH bonds in the GG–TR complex are found to
be less stable than the GG–DC and GG–PR complexes and
also, ED charges in the (s*) anti bonding orbitals of the NZH
are also one of the factors to stabilise the above base pair
complexes.
3.4 ED difference map
The ED difference map was plotted for the most stable
complexes GG –DC, GG – PR, and GG – TR at B3LYP/6-
311 þ G** level of theory. It gives a pictorial represen-
tation of the ED distribution corresponding to the above-
mentioned interactions. The concentration of ED increases
between the proton and the proton acceptor, with a
corresponding ED deficiency at the position of a proton
and the acceptor lone pair. The ED difference maps of the
most stable GG – DC, GG – PR and GG – TR drug-
interacting complexes are shown in Figure 6. It provides
the information about gain or loss of ED within the
interacting molecules.[63,64] In Figure 5, the blue region
represents the gain in ED as a result of the drug interaction,
the red regions refer to the loss of ED with the contour
values of 0.03 e/a.u.3. In the complexes GG – DC and GG –
PR, the maximum amount of ED is gained at the proton
acceptor region and less amount of ED is lost at the proton
donor moiety. However, in the GG –TR complex, a
comparatively less amount of ED is gained and lost by
their respective proton acceptors and donors. These results
confirm that the maximum amount of charge localisation
 18 R. Shankar et al.
and delocalisation in GG – DC and GG – PR is responsible
for strong interaction. Hence, the DC and PR molecules
could be potential drugs for DNA interactions.
3.5 Polarisability and dipole moment
In this study polarisability and dipole moment of the drug
molecules (DC, PR and TR) were calculated at M05-2X/6-
311 þ G** and MP2/6-311 þ G** level of theories from
the B3LYP/6-311 þ G** optimised geometry. The
calculated results revealed that the DC, PR and TR drug
molecules had significant values of dipole moment and
polarisability at the above level of theories. In general, the
drug with high polarisability and dipole moments are
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preferred for the dispersion and electrostatic interactions
in the DNAs.[49,65 –70] Similarly, in the present case DC
drug molecules had dipole moments and polarisability
values of 11.50, 11.02 D and 184, 180 a.u. at M05-2X/6-
311 þ G** and MP2/6-311 þ G** levels of theory,
respectively. For PR drug molecules, the dipole moments
values were found to be 4.70, 4.53 D and the polarisability
values were found to be 171, 168 a.u. at M05-2X/6-
311 þ G** and MP2/6-311 þ G** levels of theory.
Similarly, for the TR drug molecules, the dipole moment
and polarisability values were found to be 4.32, 3.92 D and
147, 141 a.u. at M05-2X/6-311 þ G** and MP2/6-
311 þ G** levels of theory, respectively. From the
obtained results, we have confirmed that the polarisability
and dipole moment were found to be at maximum for DC
and PR drug molecules rather than the TR drug molecule.
Deepa et al. [67], from our group, reported that a drug
should be designed with high polarisability and dipole
moment to increase the interaction between the drugs and
DNA bases. Furthermore, it was also confirmed that the
drugs with high polarisablility are good electron acceptors,
and both the normal and mismatch base pairs are good
electron donors, which leads to interaction between these
two systems. The higher polar values of the drug
molecules tend to alter the hydrogen bonded network
and produce structural distortions around the amine and
amide bonds which may reduce the p-electron conjugation
and destabilise the DNA base pairs.[49,69,70] Hence, DC
and PR drug molecules interacted well with the distorted
DNA base pairs. The obtained results reveal that the highly
polar DC and PR drugs are more suitable to inhibit the
replication of DNA base pairs, and sequentially prevent
the redundant cell growth responsible for cancer cells.
4. Conclusion
The geometry of normal base pairs, selected mismatch
base pairs and the drug –DNA complex has been analysed
using B3LYP/6-311 þ G**, M05-2X/6-311 þ G** and
MP2/6-311 þ G** levels of DFT and ab initio methods.
The optimised geometries of the normal and mismatch
base pairs are almost planar whereas the geometries of
drug-interacting complexes deviate from planarity. The
drug molecules DC and PR interacted strongly with the
GG base pairs through hydrogen bond interactions, which
alter the geometry of base pairs. The presence of steric
hindrance and p-bond overlaps between CZC bonds that
are highly delocalised in the complexes leads the planarity
of the four- and five-member rings of the base pairs to
highly diverge from the plane. Among the isolated
(without drug) normal and mismatch base pairs we chose,
GG base pair has the largest interaction energy and AT has
the smallest interaction energy. The two-body interaction
energy calculated for the isolated base pairs (DEiso) is
found to be higher than that of the corresponding base pair
in drug-interacted complexes, which shows that the
interaction between base pairs is decreased due to the
interaction of the drug molecule. Among the three drugs
chosen, DC and PR bonded well with normal and
mismatch base pairs with large interaction energy. The
presence of large number of amino and amine functional
groups has increased the number of by bifurcated
hydrogen bond interactions in the DC and PR complexes,
which leads to high charge transfer and structural stability,
but in the case of TR complexes, the above-mentioned
functional groups are found to be fewer. The nature of
hydrogen bonds in the isolated base pairs and intercalating
complexes has been studied through AIM and NBO analysis.
From the AIM analysis, inverse correlation between
topological parameters (ED and Laplacian of ED) with
respect to hydrogen bond length has been ascertained. The
NBO results reveal that, for the DC and PR complexes, the
bifurcated interactions maybe play a major role in the charge
transfer and lead to the most stable state of the above-
mentioned base pair. The ED difference maps clearly
illustrate the delocalisation of the ED in the drug-interacting
complexes. The high polarisability and dipole moment
values of drug DC make it more preferential for the
dispersion and electrostatic interactions in the DNA. From
this study, it has been concluded that the interaction of drug
molecules (DC and PR) with DNA base pairs can control the
replication of DNA or inhibit the cancer cells by blocking the
division of the cells resulting in cell death.
Acknowledgements
The authors thank the Department of Science and Technology
(DST) India for awarding this research project under the Fast
Track Scheme.
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