Download Computational Studies on Effects of MDMA as an Anticancer Drug

Chem Biol Drug Des 2010; 76: 425–432
ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.01027.x
Research Article
Computational Studies on Effects of MDMA as an
Anticancer Drug on DNA
Siavash Riahi1,2,*, Solmaz Eynollahi2 and
Mohammad R. Ganjali2,3
ties and high schools even though the side-effects of MDMA on
the human body are those such as: neuronal damage and DNA
damage (2,3).
1
Institute of Petroleum Engineering, Faculty of Engineering,
University of Tehran, Tehran, Iran
2
Center of Excellence in Electrochemistry, Faculty of Chemistry,
University of Tehran, P. O. Box 14155-6455, Tehran, Iran
3
Endocrinology & Metabolism Research Center, Tehran University of
Medical Sciences, Tehran, Iran
*Corresponding author: Siavash Riahi, [email protected]
This research is designed to further understand the
effects of the novel drug MDMA on biologic receptor of DNA. The ultimate goal is to design drugs
that have higher affinity with DNA. Understanding
the physicochemical properties of the drug as well
as the mechanism by which it interacts with DNA
should ultimately enable the rational design of
novel anticancer or antiviral drugs. Molecular modeling on the complex formed between MDMA and
DNA presented this complex to be fully capable of
participating in the formation of a stable intercalation site. Furthermore, the molecular geometries
of MDMA and DNA bases (Adenine, Guanine, Cytosine, and Thymine) were optimized with the aid of
the B3LYP ⁄ 6-31G* method. The properties of the
isolated intercalator and its stacking interactions
with adenineÆÆÆthymine (AT) and guanineÆÆÆcytosine
(GC) nucleic acid base pairs were studied with the
DFTB method. DFTB method is an approximate
version of the DFT method that was extended to
cover the London dispersion energy. The B3LYP ⁄ 631G* stabilization energies of the intercalatorÆÆÆbase pair complexes were found to be )9.40
and
)12.57 kcal ⁄ mol
for
ATÆÆÆMDMA
and
GCÆÆÆMDMA, respectively. Results from comparison
of the DFTB method and HF method conclude close
results and support each other.
Key words: DFTB, DNA, drug design, intercalator, MDMA, stacking
interaction
Received 3 November 2009, revised 13 May 2010 and accepted for
publication 22 August 2010
MDMA (3,4-methylenedioxy-N-methylamphetamine) is a ring-substituted amphetamine derivative that is structurally related to hallucinogenic drugs (1). Nowadays, MDMA used as ''ecstasy'' is
becoming increasingly widespread among young adults in universi-
In recent years, the DFT method was applied in different branches of
chemistry (4–11)a. This paper presents the recently introduced approximate DFT method, DFTB technique (density functional tight-binding),
empirical London dispersion energy term, which is accurate and
reliable for computational studies (12), and calculations performed
using the DFTB technique for H-bonded and stacked DNA base pairs
(13). Furthermore, this computationally very efficient procedure can
yet be used in quantum mechanical (QM) and QM ⁄ molecular mechanical (MM) MD simulations very conveniently and accurately (14,15).
The quantum mechanical description of interactions between
MDMA and DNA base pairs (Watson–Crick base pairing) employing
the DFTB method are reported in this paper. To achieve this goal,
MDMA and DNA base pairs were simulated; atomic charges, geometrical values (bond lengths, bond angles and dihedral angles),
dipole moment, polarizability, and energies of the frontier molecular
orbitals [high occupied molecular orbital (HOMO) and low unoccupied molecular orbital (LUMO)] were obtained. According to a literature survey, this is the first paper that studies MDMA and DNA
base pair intercalations using the DFT method.
In recent years, the DFT method was applied in different branches
of chemistry (16–22). In this paper, we have used DFTB technique
(density functional tight-binding), which is accurate and reliable for
computational studies, especially for H-bonded and stacked DNA
base pairs (23,24).
The aim of this work was to study the geometries, electronic
MDMA structures and its molecular complexes with nucleobases by
DFTB methods. This study will shed more light on the nature of
intercalations between a drug and DNA dominantly from the viewpoint of charge transfer, dispersion, and electrostatic forces. Hence,
the study can help design new intercalators (drugs) that have higher
affinity with DNA.
Computational Methods
Calculations on isolated molecules and molecular complexes were
performed with GAUSSIAN 98 package (25).
Both species were initially optimized with PM3 method. The
optimized structures were again optimized with density functional
425
Riahi et al.
theory using the 6-31G* basis set. Full geometry optimizations and
frequency calculations were performed, and each species was found
to be at minima, by having no negative values in the frequency calculation. The calculations gave internal energies at 0 K. To obtain
gas-phase free energies at 298.15 K, it is necessary to calculate
the zero-point energies and thermal corrections together with entropies to convert the internal energies to Gibbs energies at 298.15 K
(26,27).
Frequency calculations on these structures verify that they were at
true minima and provided necessary thermal corrections to calculate
H (Enthalpy) and G (Gibbs free energy). Finally, full optimizations
and frequency calculations for each species were performed with
the HF ⁄ 6-31G* and DFT ⁄ 6-31G* (28,29).
The MDMA structure and geometry were optimized at the B3LYP
level using the 6-31G* basis set. To find the most stable equilibrium structure for MDMAÆÆÆBase pairs complexes, the initial guess
structures are considered based on PM3 semiempirical calculations. Full geometry search based on Newton–Rapson procedure
as implemented in GAMESS quantum chemistry code were followed (30). The most stable geometries were achieved when the
intercalator (MDMA) and base pairs adenineÆÆÆthymine and guanineÆÆÆcytosine (AT and GC) were situated in coplanar planes in such
a way that the major system axes were parallel. There is special
definition for the molecular geometries of DNA base pairs. In all
cases, the QM-optimized geometries of the base pairs and intercalators were used for QM calculations. Thus, when the idealized
geometries were utilized, the interacting molecules were overlaid
by their HF ⁄ 6-31G* and B3LYP ⁄ 6-31G* optimized geometries,
based on the least-squares fitting method. In the case of empirical
potential calculations, either the subsystem geometries were
relaxed by the empirical potential or the QM-optimized geometries
were saved. This difference had an insignificant effect on the calculated energies.
The other one-electron properties (dipole moment, polarizability,
energies of the frontier molecular orbital) were also determined at
the HF ⁄ 6-31G* and B3LYP ⁄ 6-31G* level. For charged species, the
dipole moment was derived with respect to their mass center,
because for the non-neutral molecules, the calculated dipole moment
depends on the origin of the co-ordinate system. Dipole moment
refers to the quality of a system to behave like a dipole. Dipole
moment is the measured polarity of a polar covalent bond and is
defined as the product magnitude of charge on the atoms and the
distance between the two bonded atoms. Polarizability is the relative
tendency of a charge distribution, like the electron cloud of an atom
or molecule, to be distorted from its normal shape by an external
electric field.
The stabilization energies of selected complexes were determined
by DFT calculations and calculated with a recently introduced
method based on the combination of the approximate tight-binding DFTB with the empirical dispersion energy. The DFT methods
are known to be inherently very deficient for stacking interactions as they basically ignore the dispersion attraction (31–33).
As a consequence, their enlargement by an empirical dispersion
term currently appears to be a very reasonable way to improve
426
the major deficiency of the DFT method for the evaluation of
the molecular complexes. It should also be mentioned that interaction energies were obtained as the difference between the
complex energy and the combined energies of the molecules in
isolation (34).
Processes in DNA environment depend on a delicate balance
between stacking interactions, hydrogen bonding and hydration
effects (35). Hydration free energies could be calculated by implicit
models like solvent reaction field (36) and Langevin dipole (37)
methods, or by explicit models in conjunction with free energy calculations and molecular dynamics simulations (38). Because of complexity of these calculations, hydration effects will be evaluated in
future studies.
Results and Discussion
MDMA characteristics
The optimized structure, atom numbering, and atom charges of
MDMA are shown in Figure 1. The equilibrium geometries of the
MDMA subsystem were determined and confirmed by subsequent
calculations of the vibrational frequencies. Geometrical optimizations were performed using the DFTB method, and the significant
computed geometrical parameters are available in Table 1. This
table contains significant geometrical values including: bond length,
bond angles, and dihedral angles for MDMA, before and after the
complex formation (MDMAÆÆÆAT and MDMAÆÆÆGC).
MDMA does not have a planar structure – in fact, it illustrates
one equal branch that is entirely out of plane (it demonstrate 73
out of planarity of the whole geometry). It should also be mentioned that the atom charge distribution in the MDMA is delocalized. Carbons 7 and 11 exhibit the highest positive charges, which
are the cause of them bonding to the oxygen atoms with high
electronegativity. The most negative charge is N2 because it is in
close vicinity to hydrogen and carbon, which are electropositive
atoms. O8 and O10 are electronegative atoms but they connect to a
benzene ring that is electron withdrawing, so they are not the
most negatively charged. The presence of electronegative elements
in MDMA facilitated its interaction with the DNA molecule through
hydrogen bonding with GC and AT hydrogen. Actually, there are
two kinds of interactions between MDMA and DNA; electrostatic
interactions and dispersion interactions, being discussed in the next
paragraphs.
Table 2 depicts the one-electron properties (dipole moment and
polarizability) and the energies of the frontier molecular orbital
(HOMO and LUMO) of MDMA using the DFTB and HF computational
method. For validation of the results, HF and DFTB methods were
applied. The results are close, and each method confirms other
method. Because of the DFTB method covers the London dispersion
energy, this method is more accurate. Dipole moment is the first
derivative of energy with respect to an applied electric field as a
measure of asymmetry in the molecular charge distribution. High
values of dipole moment and polarizability show that electrostatic
and dispersion contribution play a key role in the interaction with
nucleobases.
Chem Biol Drug Des 2010; 76: 425–432
Effects of MDMA as an Anticancer Drug on DNA
0.109
A
0.139
0.272
–0.255
0.102
0.151
–0.570
–0.335
0.144
0.128
–0.131
0.094
0.138
-0.557
0.294
0.146
–0.395
0.176
0.094
0.140
0.141
0.196
0.177
0.128
0.255
–0.556
–0.107
0.147
B 0.158(0.151)
0.264(0.270)
0.113 (0.130)
0.106(0.104)
–0.257(–0.256)
–0.141(–0.130)
–0.330(–0.341)
–0.570(–0.570)
0.057(0.058)
–0.400(–0.396)
0.137(0.136)
0.131(0.141)
0.134(0.135)
–0.638(–0.651)
0.256(0.250)
0.168(0.180)
0.222(0.193)
0.170(0.165)
0.089(0.096)
–0.180(–0.184)
0.127(0.124)
0.265(0.259)
–0.662(–0.660)
–0.108(–0.102)
0.152(0.159)
Figure 1: (A) The optimized structure and the atom charges of MDMA. (B) The optimized structure and the atom charges of MDMA after
the complex formation with GC and AT (Parentheses include the changes after the complex formation with AT).
Table 1: Significant computed geometrical parameters for MDMA before and after complex formation
Bond
lengths
MDMA
MDMA- GC
MDMA- AT
R(2,3)
R(7,8)
R(8,9)
R(9,10)
R(9,24)
1.473
1.407
1.473
1.472
1.091
1.476
1.402
1.481
1.478
1.088
1.474
1.406
1.471
1.475
1.094
Bond
angles
MDMA
MDMA - GC
MDMA - AT
A(1,2,18)
A(3,2,18)
A(4,5,6)
A(7,8,9)
A(9,10,11)
A(10,11,12)
111.9
111.6
119.7
106.2
106.2
128.1
111.4
111.0
119.3
105.5
105.8
127.7
111.6
111.3
119.5
105.9
105.8
128.4
Base pairs characteristics
Optimized structures of adenineÆÆÆthymine (AT) and guanineÆÆÆcytosine
(GC) base pairs in the Watson–Crick structures are visualized in
Figures 2 and 3, respectively. Tables 3 and 4 show the significant
computed geometrical parameters, using the DFTB method before
and after complex formation. In addition, Table 2 presents the oneelectron properties (dipole moment and polarizability) and energies
of the frontier molecular orbital (HOMO and LUMO) of bases and
base pairs. From Table 2, it is clear that all bases and base pairs
Chem Biol Drug Des 2010; 76: 425–432
Bond
dihedrals
MDMA
MDMA - GC
MDMA - AT
D(6,7,8,9)
D(11,7,8,9)
D(7,8,9,10)
D(7,8,9,23)
D(7,8,9,24)
D(8,9,10,11)
D(23,9,10,11)
D(24,9,10,11)
D(9,10,11,7)
D(9,10,11,12)
179.8
0.1
)0.1
)118.4
118.2
0.1
118.4
)118.2
0.0
)179.7
170.4
)10.3
14.6
)102.9
131.9
)13.6
103.9
)130.8
7.6
)165.7
)174.5
8.0
)11.9
)129.8
106.0
11.4
128.8
)106.7
)6.8
175.2
are very poor electron acceptors (all LUMO energies are positive in
contrast to LUMO energy of MDMA, which is negative). In this scenario, bases and base pairs are good electron donors, and among
the isolated bases, the best one is guanine. This is in accordance
with experimental and theoretical studies showing that ultimate
carcinogens primarily react with DNA at the N7 atom of guanine
(39,40). Base pairing can also further magnify electron donor ability.
For example, the HOMO energy of guanine ()8.45 eV) increases
by 1.1 eV upon pairing with cytosine. Furthermore, the high polariz427
Riahi et al.
Table 2: Dipole moment [D], polarizability [B3], HOMO, and LUMO energies (in eV) of the drug, the bases and the base pairs with HF and
DFTB methods
HOMO
LUMO
Dipole moment
Polarizability
Compound
DFTB
HF
DFTB
HF
DFTB
HF
DFTB
HF
AT
GC
MDMA
A
T
G
C
)8.64
)7.35
)5.54
)8.83
)9.53
)8.45
)9.93
)8.21
)7.56
)5.30
)8.43
)9.57
)8.11
)9.22
3.01
2.74
)0.08
3.12
2.94
3.52
3.01
3.27
2.92
)0.13
3.74
3.26
4.13
3.30
1.28
2.51
0.90
2.49
3.88
2.76
6.12
1.18
2.22
0.89
2.52
3.32
2.56
7.97
213.2
223.4
174.3
101.2
89.1
109.2
80.4
201.6
215.6
154.3
96.1
85.1
100.7
83.6
0.246(0.346)
–0.364(–0.450)
–0.418(–0.690)
0.128(0.188)
0.118(0.173)
0.491(0.694)
0.162(0.161)
–0.457(–0.740)
–0.337(–0.358)
0.237(0.340)
0.358(0.426)
– 0.512(–0.585)
0.304(0.438)
0.220(0.119)
–0.337(0.053)
0.097(0.134)
0.472(0.524)
– 0.390(– 0.709)
0.170(0.256)
–0.476(–0.779)
0.115(0.177)
–0.225(–0.457)
0.492(0.532)
–0.104(0.075)
0.129(0.171)
–0.410(–0.500)
0.129(0.165)
0.260(0.388)
–0.335(–0.414)
0.237(0.341)
Figure 2: Optimized structure and charge of AT base pair & MDMAÆÆÆAT before and after the complex formation (Parentheses include the
changes after the complex formation).
ability and dipole moment values of AT and GC (but more than
those of MDMA) reveal that the electrostatic and dispersion
contribution considerably influence the interaction with the intercalator.
From previous papers, we can understand that the DFT method is
more accurate. Moreover, the results conclude from the comparison
of the DFTB method and HF method that these both show similar
results and support each other.
Complex characteristics
The MDMAÆÆÆAT and MDMAÆÆÆGC optimized geometries are summarized in Figures 4A, B, respectively. The atom charge differences of
MDMA, AT, and GC are presented in Figures 1A,B, 2 and 3, respectively. From Figure 1B, it is obvious that the charge difference after
the complex formation is greater. For instance, in GCÆÆÆMDMA, C7
and C11, the atom charge differences are 0.256 and 0.265, respectively. In contrast, the oxygen charge moves to more negative values (i.e., for O8 and O10, the atom charge shifts from )0.557 and
)0.556 to )0.638 and )0.662, respectively). These changes indicate
that oxygen receives a part of its charge from the hydrogen atoms
428
in GC. Hence, weak hydrogen bonding was formed between MDMA
and GC.
The study of atom charges in GC and MDMAÆÆÆGC exhibits that the
part shown with dash marks (the only part that is going to be discussed afterward) displays the highest changes because of MDMA
and GC interactions. Similar changes have also been obtained in
AT. Because the MDMA heteroatoms interact with GC hydrogen in
the zone, the charge changes are not important for the other heteroatom of GC or AT bases pairs. This observation was proven by
the increase in GC hydrogen charges (i.e., H26 atom charge shifted
from 0.304 to 0.438), revealing a stronger hydrogen bond had been
formed between these atoms and the heteroatoms in the drug and
the decrease in their bond length (i.e., R bond length (2, 26) shifted
from 1.910 to 1.851).
After interaction with the MDMA, molecule bond angles of base
pairs changed in the mentioned area, i.e., in GC, A (1, 10, 29)
shifted from 117.2 to 125.6. The changes in dihedral angles denote
that the base pair structures have shifted from planar, i.e., D
(1,2,10,29) in GC displays the highest difference. As it is evident
from Tables 1 and 3, bond lengths, bond angles, and dihedral
Chem Biol Drug Des 2010; 76: 425–432
Effects of MDMA as an Anticancer Drug on DNA
0.229(0.327)
–0.428(–0.508)
0.244(0.349)
–0.501(–0.788)
0.262(0.393)
0.502(0.638)
0.564(0.666)
–0.416(–0.415)
0.228(0.330)
0.354(0.446)
–0.406(–0.669)
0.194(0.156)
–0.522(–0.553)
–0.491(–0.772)
0.472(0.557)
–0.393(–0.722)
–0.278(–0.141)
0.282(0.419)
0.439(0.495)
–0.449(–0.763)
–0.153(0.046)
0.129(0.182)
0.109(0.151)
0.151(0.250)
0.286(0.408)
–0.443(–0.554)
0.228(0.321)
–0.301(–0.389)
0.106(0.166)
Figure 3: Optimized structure and charge of GC base pair & MDMAÆÆÆGC, before and after the complex formation (Parentheses include the
changes after the complex formation).
Table 3: Significant computed geometrical parameters for GC and MDMA before and after the complex formation
Bond lengths
GC
GC-MDMA
Bond angles
GC
GC-MDMA
Bond dihedrals
GC
GC-MDMA
R(1,2)
R(1,10)
R(2,3)
R(2,12)
R(2,26)
R(3,11)
R(10,29)
R(11,15)
R(11,16)
R(12,22)
R(17,22)
R(17,23)
R(21,22)
R(21,24)
R(23,28)
R(23,29)
1.409
1.233
1.4373
1.032
1.910
1.348
1.8764
1.020
1.004
1.909
1.335
1.334
1.4357
1.228
1.005
1.035
1.466
1.312
1.475
1.051
1.851
1.431
1.789
1.031
1.037
1.867
1.408
1.343
1.442
1.311
1.023
1.020
A(2,1,10)
A(1,2,3)
A(1,2,12)
A(3,2,12)
A(2,3,11)
A(1,10,29)
A(3,11,15)
A(3,11,16)
A(15,11,16)
A(22,17,23)
A(22,21,24)
A(17,22,21)
A(17,23,28)
A(17,23,29)
A(28,23,29)
119.9
125.9
115.2
118.9
116.8
117.2
123.1
116.7
120.3
117.9
124.6
121.4
120.1
120.6
119.3
118.9
124.9
115.3
119.5
117.4
125.6
122.9
116.8
120.2
117.8
124.2
121.4
120.4
119.9
118.4
D(10,1,2,3)
D(10,1,2,12)
D(2,1,10,29)
D(1,2,3,11)
D(12,2,3,11)
D(2,3,11,15)
D(2,3,11,16)
D(1,10,23,17)
D(1,10,23,28)
D(23,17,22,21)
D(22,17,23,28)
D(22,17,23,29)
D(24,21,22,17)
)180.0
0.0
0.0
)180.0
0.0
)0.1
)180.0
0.1
)180.0
)180.0
)180.0
0.0
)180.0
177.3
)8.1
22.4
178.6
4.2
)2.4
)179.7
)24.0
174.1
)178.7
178.4
11.4
177.6
angles alter significantly in a way that the hydrogen bonding
becomes weak, causing changes in the DNA molecular structure.
Therefore, drugs should be designed that bring about the least
changes in DNA and its molecular structure. To avoid repetition, the
results attained for AT are only listed in Table 4 and Figure 2,
which are in agreement with those of GC.
In general, a way for data collection regarding the electron distribution is by computing the polarizability. This property depends on the
second derivative of the energy relating to an electric field. Table 2
delineates the high MDMA, GC, and AT polarizability values,
supporting the fact that the dispersion energy is always important.
Chem Biol Drug Des 2010; 76: 425–432
Another way is dipole moment of base pairs and the studied intercalator, which is presented in Table 2. The significant polarizability
and dipole moment values prove the existence of dispersion and
electrostatic interactions between DNA and MDMA. The polarizability and dipole moment of intercalator have the same effects on the
interaction with DNA. Hence, a drug should be designed with high
polarizability and dipole moment to increase the interactions
between DNA and the drug.
To evaluate the dependence of the Intercalator–Base Pair Stacking
interaction energy on their vertical separation, investigations were
carried out with the vertical distance between the interacting sys429
Riahi et al.
Table 4: Significant computed geometrical parameters for AT and MDMA before and after the complex formation
Bond lengths
AT
AT-MDMA
Bond angles
AT
AT-MDMA
Bond dihedrals
AT
AT-MDMA
R(1,2)
R(1,10)
R(2,3)
R(2,26)
R(3,12)
R(10,13)
R(10,14)
R(16,18)
R(16,24)
R(18,19)
R(18,26)
R(19,23)
1.351
1.341
1.346
1.823
1.086
1.020
1.006
1.380
1.214
1.389
1.046
1.229
1.367
1.345
1.359
1.713
1.083
1.024
1.008
1.381
1.248
1.390
1.060
1.263
A(2,1,10)
A(1,2,3)
A(1,2,26)
A(3,2,26)
A(2,3,12)
A(1,10,13)
A(1,10,14)
A(13,10,14)
A(18,16,24)
A(16,18,19)
A(16,18,26)
A(19,18,26)
A(18,19,23)
119.7
119.7
123.2
117.1
114.8
120.7
118.6
120.6
124.4
127.1
115.9
117.0
120.8
119.3
120.6
122.8
116.3
115.4
120.5
119.3
120.2
124.1
126.5
116.0
117.4
120.6
D(10,1,2,3)
D(10,1,2,26)
D(2,1,10,13)
D(2,1,10,14)
D(1,2,3,12)
D(26,2,3,12)
D(1,2,18,16)
D(1,2,18,19)
D(3,2,18,16)
D(3,2,18,19)
D(24,16,18,19)
D(24,16,18,26)
D(16,18,19,23)
D(26,18,19,23)
180.0
0.0
0.0
180.0
180.0
0.0
)180.0
0.0
0.0
179.9
)180.0
0.0
)180.0
0.0
)179.0
7.6
1.2
)177.2
)178.5
)4.7
162.9
)12.3
)9.4
175.4
179.4
2.7
179.8
)3.5
A
2
A
0
–2
–4
–6
B
E (kcal/mol)
–8
–10
B
25
20
15
10
5
0
–5
–10
Figure 4: (A, B) Optimized structures of MDMA ÆÆÆAT and MDMA
ÆÆÆGC, respectively.
tems. The interaction energies were corrected for the basis set
superposition error using the counterpoise method (41,42).
Figures 5A, B illustrate the investigated structures for AT and GC
with MDMA, respectively. As it is apparent from Figures 5A, B, the
minimum values of the respective potential energy curve for
ATÆÆÆMDMA and GCÆÆÆMDMA were found at 4.35 and 4.02 ,
respectively. The stabilization energies (energy necessary to separate MDMA and AT pair to infinity) of ATÆÆÆMDMA and GCÆÆÆMDMA
were equal to )9.40, )7.95 and )12.57, )10.88 kcal ⁄ mol, by DFTB
and HF methods, respectively. Consequently, as the interaction
430
–15
2
4
r (Å)
6
Figure 5: Stabilization energies (DE) of MDMA ÆÆÆAT (A) and
MDMA ÆÆÆGC (B), r is the distance between base pairs and drug
molecule.
energy increases, the distance between the DNA molecule and drug
reduces. In addition, computational chemistry methods as a kind of
extension of the experimental approach have a great interest in
chemotherapy studies of DNA-drug binding. These theoretical studies are used to predict convenient structures of DNA-drugs binding
to control the DNA changes.
Chem Biol Drug Des 2010; 76: 425–432
Effects of MDMA as an Anticancer Drug on DNA
It is evident that only the theoretical procedures properly cover the
dispersion and polarization effects; therefore these procedures were
used for the study of intercalation processes and designing a drug
that has higher affinity with DNA molecules.
Acknowledgments
We gratefully acknowledge the support of this work by the Institute
of Petroleum Engineering, Tehran University Research Councils.
References
Figure 6: Optimized structures of MDMA with different DNA
double base pairs.
The evaluation of the BSSE was carried out that for MDMA-GC and
MDMA-AT were equal to 3.347 and 3.590 kcal ⁄ mol, respectively.
Interaction between MDMA and DNA did not happen with only single base pair. Actually, intercalators bind with whole molecule of
DNA and total SNA structure is important. In computational methods,
at least interaction with a double base pair is recommended (43). So,
the intercalation reaction between MDMA and different double base
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optimized with PM3 method. Because of the 3D geometries of
MDMA and double base pairs of DNA were similar, one of them was
shown in Figure 6.
Conclusion and Future Directions
MDMA is a good electron acceptor with high polarizability. In contrast, AT and GC base pairs are good electron donors. These outcomes are very favorable for aromatic stacking interactions
between these two systems. In designing a drug, changes in the
structure and addition of specific groups should be to increase values of the main parameters such as polarizability, dipole moment,
and interaction energy. With high values of these factors, it can be
concluded that the drug design is suitable.
Chem Biol Drug Des 2010; 76: 425–432
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Note
a
[Online] available: http://www2.netdoctor.co.uk/medicines/100001882.html.
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