Quantum Chemical Studies of Anti-Prostatic Carcinoma Drug N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]
Propanamide (bicalutamide).
I.E. Otuokere and F J Amaku
Department of Chemistry,
Michael Okpara University of Agriculture, Umudike, Nigeria
*Corresponding Author E-mail:
ABSTRACT:
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide
(bicalutamide) is an
oral medication that is used for treating cancer of the prostate. It belongs to
a class of drugs called anti- androgens. Quantum chemical studies of bicalutamide were based on Arguslab
software. The steric energy was evaluated in
terms of potential energy as a sum of energies associated with bonded
interactions (bond length, bond angle
and dihedral angle) as well as non-bonded interactions (van der
Waals and electrostatic). Surfaces were created to visualize excited state
properties such as highest occupied molecular orbital’s, lowest unoccupied
molecular orbital’s and electrostatic potential (ESP) mapped density. The steric energy for bicalutamide was calculated to be
0.963933 a.u. (604.877867 kcal/mol). The most
energetically favourable conformation of bicalutamide was found to have a heat of formation of
7696.375900 kcal/mol. The self-consistent field (SCF) energy was calculated by
geometry convergence function using RHF/PM3 method in ArgusLab
software. The most feasible position for bicalutamide to block androgen receptors on the
cells of tissues was found to be -189.888176 au ( -119156.737100 Kcal/mole).
KEYWORDS:
Arguslab software, bicalutamide, steric energy, receptors, surfaces.
INTRODUCTION:
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide
(bicalutamide)
is an oral medication that is used for treating cancer of the prostate [1].
It belongs to a class of drugs called anti-androgens which includes flutamide and nilutamide. Androgens are hormones that are produced and
released by the adrenal glands [2] . They are responsible for
supporting (stimulating) tissues that primarily are thought of as male, such
as, the male prostate gland. Male traits that are influenced by androgens
include facial and body hair, and small breasts. Anti-androgens prevent the
action of androgens by blocking androgen receptors on the cells of tissues, for
example, the cells of the prostate gland [3].
In addition to normal
prostate cells, androgens also have been shown to stimulate the growth of
cancer cells within the prostate. Bicalutamide is thought to prevent the growth
of prostate cancer by blocking the effects of androgens on the cancer
cells [4]. Bicalutamide was approved by
the FDA in 1995. Bicalutamide has been
tested with good results for metastatic
breast cancer in a phase II study and is used off-label for
this indication[5,6,7].
The geometry of a molecule has a great impact on
its energy level, physical and chemical properties. As the molecule rotates, it
adopts different conformations and spatial arrangements to achieve a stable
state with the lowest energy[8]. The total molecular energy can be
evaluated in terms of potential energy surface as a sum of energies associated
with each type of bonded interactions i.e. bond length, bond angle and dihedral
angle as well as non-bonded interactions (Vander Waals and electrostatic)
taking place in a molecule [9]. This present work describes the quantum
chemical studies of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide
(Bicalutamide) by ArgusLab 4.0.1
software [10].
MATERIALS AND METHODS:
A computational conformational analysis and
geometry optimization study of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide
was performed on a window based computer using Arguslab
[10] and ACDlab
ChemSketch[11] software. ACDlab ChemSketch software was
used to generate the electron density cloud of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]
propanamide. N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide structure was generated by ArgusLab 4.0.1[10] and geometric optimization was performed with
the semi-empirical RHF/Austin Model 1 (AM1) parameterization. The minimum
potential energy was calculated by using geometry convergence function in Arguslab software [10].
In order to determine the allowed conformation the contact distance between the
atoms in adjacent residues was examined using criteria for minimum Vander Waal
contact distance [12]. Surfaces created to visualize the excited
state properties such as orbital, electron densities, electrostatic potentials
(ESP) mapped density. The final geometrical energy and SCF energy was
calculated by RHF/PM3 method, as performed by Arguslab
4.0.1 suite.
RESULTS AND DISCUSSION:
Figure. 1 shows the perspective view of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methyl-3-[(4-methylphenyl)sulfonyl]propanamide
(bicalutamide)
generated by ACDlab
Chemsketch. Electron density and active conformation
of bicalutamide
with labeled atoms genetated
by Arguslab software is illustrated in Figures 2 and
3. Figure 4 and 5 illustrates the
frontier molecular orbital’s i.e. highest occupied molecular orbital (HOMO) and
the lowest unoccupied (LUMO) molecular orbital. Figure 6 represent the opaque
electrostatic potential (ESP) mapped electron density surface. SCF energy
convergence map is shown in Figure 7. Atomic coordinates are given in Table 1.
Tables 2 and 3 represent the bond angles and bond lengths respectively. Tables
4 and 5 represent dihedral angles and Mulliken / ZDO
atomic charges of bicalutamide, Estimated steric energy for bicalutamide
calculated from geometry optimization is shown in Table 6.
Figure 2: Electron density clouds of bicalutamide by ACDlabs 3D
viewer.
Figure 3: Active conformation
of bicalutamide by Arguslab
software.
Figure 4: Highest occupied
molecular orbital’s (HOMO) of bicalutamide.
Figure 5: Lowest unoccupied
molecular orbital’s (LUMO) of bicalutamide.
Figure 6: Electrostatic
potential mapped density of bicalutamide.
Figure 7: SCF energy of bicalutamide.
Table 1: Atomic coordinates of bicalutamide.
|
S.
No |
Atoms |
x |
y |
z |
|
1 |
C |
15.221000 |
-14.029100 |
0.000000 |
|
2 |
C |
15.221000 |
-15.359100 |
0.000000 |
|
3 |
C |
14.069100 |
-13.364100 |
0.000000 |
|
4 |
C |
14.069100 |
-16.024100 |
0.000000 |
|
5 |
C |
12.917300 |
-14.029100 |
0.000000 |
|
6 |
C |
12.917300 |
-15.359100 |
0.000000 |
|
7 |
N |
14.069100 |
-12.034100 |
0.000000 |
|
8 |
C |
15.220900 |
-11.369100 |
0.000000 |
|
9 |
O |
15.220800 |
-10.039100 |
0.000000 |
|
10 |
C |
16.372700 |
-12.034100 |
0.000000 |
|
11 |
C |
16.372700 |
-13.364100 |
0.000000 |
|
12 |
C |
17.524500 |
-11.369000 |
0.000000 |
|
13 |
O |
16.372700 |
-10.704100 |
0.000000 |
|
14 |
C |
14.069100 |
-17.354100 |
0.000000 |
|
15 |
C |
16.372800 |
-16.024100 |
0.000000 |
|
16 |
S |
18.676300 |
-12.034000 |
0.000000 |
|
17 |
O |
19.341300 |
-10.882200 |
0.000000 |
|
18 |
O |
18.011300 |
-13.185800 |
0.000000 |
|
19 |
C |
19.828000 |
-12.699200 |
0.000000 |
|
20 |
C |
20.980000 |
-12.034400 |
0.000000 |
|
21 |
C |
19.827800 |
-14.029300 |
0.000000 |
|
22 |
C |
22.131700 |
-12.699700 |
0.000000 |
|
23 |
C |
20.979500 |
-14.694500 |
0.000000 |
|
24 |
C |
22.131400 |
-14.029700 |
0.000000 |
|
25 |
C |
23.283100 |
-14.694900 |
0.000000 |
Table
2: Bond length of bicalutamide.
|
Atoms
|
Bond
length |
|
(C1)-(C2) |
1.458000 |
|
(C1)-(C3) |
1.323387 |
|
(C2)-(C4) |
1.323387 |
|
(C2)-(C15) |
1.461000 |
|
(C3)-(C5) |
1.458000 |
|
(C3)-(N7) |
1.419751 |
|
(C4)-(C6) |
1.458000 |
|
(C4)-(C14) |
1.461000 |
|
(C5)-(C6) |
1.323387 |
|
(N7)-(C8) |
1.346235 |
|
(C8)-(O9) |
1.260307 |
|
(C8)-(C10) |
1.489000 |
|
(C10)-(C11) |
1.489000 |
|
(C10)-(C12) |
1.489000 |
|
(C10)-(O13) |
1.436155 |
|
(C12)-(S16) |
1.803096 |
|
(S16)-(O17) |
1.546726 |
|
(S16)-(O18) |
1.546726 |
|
(S16)-(C19) |
1.800077 |
|
(C19)-(C20) |
1.458000 |
|
(C19)-(C21) |
1.323387 |
|
(C20)-(C22) |
1.323387 |
|
(C21)-(C23) |
1.458000 |
|
(C22)-(C24) |
1.458000 |
|
(C23)-(C24) |
1.323387 |
|
(C24)-(C25) |
1.461000 |
Table
3: Bond angles of bicalutamide
|
Atoms |
Bond
angles |
Alternate
angles |
|
(C2)-(C1)-(C3) |
120.000000 |
216.488007
|
|
(C1)-(C2)-(C4) |
120.000000 |
216.488007
|
|
(C1)-(C2)-(C15) |
120.000000 |
187.861407
|
|
(C1)-(C3)-(C5) |
120.000000 |
216.488007
|
|
(C1)-(C3)-(N7) |
120.000000 |
300.697530
|
|
(C4)-(C2)-(C15) |
120.000000 |
215.760874
|
|
(C2)-(C4)-(C6) |
120.000000 |
216.488007
|
|
(C2)-(C4)-(C14) |
120.000000 |
215.760874
|
|
(C5)-(C3)-(N7) |
120.000000 |
260.801534
|
|
(C3)-(C5)-(C6) |
120.000000 |
216.488007
|
|
(C3)-(N7)-(C8) |
120.000000 |
220.592895
|
|
(C6)-(C4)-(C14) |
120.000000 |
187.861407
|
|
(C4)-(C6)-(C5) |
120.000000 |
216.488007
|
|
(N7)-(C8)-(O9) |
120.000000 |
421.698151
|
|
(N7)-(C8)-(C10) |
120.000000 |
271.876115
|
|
(O9)-(C8)-(C10) |
120.000000 |
268.043115
|
|
(C8)-(C10)-(C11) |
109.470000 |
225.183707
|
|
(C8)-(C10)-(C12) |
109.470000 |
225.183707
|
|
(C8)-(C10)-(O13) |
109.470000 |
285.652813
|
|
(C11)-(C10)-(C12) |
109.470000 |
225.183707
|
|
(C11)-(C10)-(O13) |
109.470000 |
285.652813
|
|
(C12)-(C10)-(O13) |
109.470000 |
285.652813
|
|
(C10)-(12C)-(S16) |
120.000000 |
182.954379
|
|
(C12)-(S16)-(O17) |
92.100000 |
302.641626
|
|
(C12)-(S16)-(O18) |
92.100000 |
302.641626 |
|
(C12)-(S16)-(C19) |
92.100000 |
206.072728 |
|
(O17)-(S16)-(O18) |
92.100000 |
471.223100 |
|
(O17)-(S16)-(C19) |
92.100000 |
303.587174 |
|
(O18)-(S16)-(C19) |
92.100000 |
303.587174 |
|
(S16)-(C19)-(C20) |
120.000000 |
188.274860
|
|
(S16)-(C19)-(C21) |
120.000000 |
210.303144
|
|
(C20)-(C19)-(C21) |
120.000000 |
216.488007
|
|
(C19)-(C20)-(C22) |
120.000000 |
216.488007
|
|
(C19)-(C21)-(C23) |
120.000000 |
216.488007
|
|
(C20)-(C22)-(C24) |
120.000000 |
216.488007
|
|
(C21)-(C23)-(C24) |
120.000000 |
216.488007
|
|
(C22)-(C24)-(C23) |
120.000000 |
216.488007
|
|
(C22)-(C24)-(C25) |
120.000000 |
187.861407
|
|
(C23)-(C24)-(C25) |
120.000000 |
215.760874
|
Table
4: Dihedral angles of bicalutamide.
|
Atoms |
Dihedral
angles |
|
(C4)-(C2)-(C1)-(C3) |
5.000000 |
|
(C15)-(C2)-(C1)-(C3) |
5.000000 |
|
(C2)-(C1)-(C3)-(C5) |
19.486776 |
|
(C2)-(C1)-(C3)-(N7) |
19.486776 |
|
(C1)-(C2)-(C4)-(C6) |
9.743388 |
|
(C1)-(C2)-(C4)-(C14) |
9.743388 |
|
(C1)-(C3)-(C5)-(C6) |
5.000000 |
|
(C1)-(C3)-(N7)-(C8) |
5.000000 |
|
(C6)-(C4)-(C2)-(C15) |
9.743388 |
|
(C14)-(C4)-(C2)-(C15) |
9.743388 |
|
(C2)-(C4)-(C6)-(C5) |
5.000000 |
|
(C6)-(C5)-(C3)-(N7) |
5.000000 |
|
(C5)-(C3)-(N7)-(C8) |
5.000000 |
|
(C3)-(C5)-(C6)-(C4) |
38.973552 |
|
(C3)-(N7)-(C8)-(O9) |
13.474221 |
|
(C3)-(N7)-(C8)-(C10) |
13.474221 |
|
(C5)-(C6)-(C4)-(C14) |
5.000000 |
|
(N7)-(C8)-(C10)-(C11) |
0.333333 |
|
(N7)-(C8)-(C10)-(C12) |
0.333333 |
|
(N7)-(C8)-(C10)-(O13) |
0.333333 |
|
(O9)-(C8)-(C10)-(C11) |
0.333333 |
|
(O9)-(C8)-(C10)-(C12) |
0.333333 |
|
(O9)-(C8)-(C10)-(O13) |
0.333333 |
|
(C8)-(C10)-(C12)-(S16) |
0.333333 |
|
(C11)-(C10)-(C12)-(S16) |
0.333333 |
|
(S16)-(C12)-(C10)-(O13) |
0.333333 |
|
(C10)-(C12)-(S16)-(O17) |
2.635231 |
|
(C10)-(C12)-(S16)-(O18) |
2.635231 |
|
(C10)-(C12)-(S16)-(C19) |
2.635231 |
|
(C12)-(S16)-(C19)-(C20) |
1.317616 |
|
(C12)-(S16)-(C19)-(C21) |
1.317616 |
|
(O17)-(S16)-(C19)-(C20) |
1.317616 |
|
(O17)-(S16)-(C19)-(C21) |
1.317616 |
|
(O18)-(S16)-(C19)-(C20) |
1.317616 |
|
(O18)-(S16)-(C19)-(C21) |
1.317616 |
|
(S16)-(C19)-(C20)-(C22) |
5.000000 |
|
(S16)-(C19)-(C21)-(C23) |
19.486776 |
|
(C22)-(C20)-(C19)-(C21) |
5.000000 |
|
(C20)-(C19)-(C21)-(C23) |
19.486776 |
|
(C19)-(C20)-(C22)-(C24) |
38.973552 |
|
(C19)-(C21)-(C23)-(C24) |
10.000000 |
|
(C20)-(C22)-(C24)-(C23) |
5.000000 |
|
(C20)-(C22)-(C24)-(C25) |
5.000000 |
|
(C21)-(C23)-(C24)-(C22) |
19.486776 |
|
(C21)-(C23)-(C24)-(C25) |
19.486776 |
Table
5: List of Mulliken atomic charges and ZDO atomic
charges of bicalutamide.
|
S.No |
Atoms |
ZDO
atomic charges |
Mulliken atomic charges |
|
1 |
C |
3.1873 |
3.2003 |
|
2 |
C |
3.1161 |
3.1048 |
|
3 |
C |
2.9111 |
2.9365 |
|
4 |
C |
3.1373 |
3.1412 |
|
5 |
C |
3.0610 |
3.0590 |
|
6 |
C |
3.0653 |
3.0600 |
|
7 |
N |
3.1659 |
3.0966 |
|
8 |
C |
1.0299 |
1.1183 |
|
9 |
O |
0.6417 |
0.5987 |
|
10 |
C |
0.5988 |
0.5764 |
|
11 |
C |
1.3712 |
1.4591 |
|
12 |
C |
-1.5922 |
-1.6155 |
|
13 |
O |
-0.6757 |
-0.6901 |
|
14 |
C |
3.5143 |
3.5188 |
|
15 |
C |
3.5524 |
3.5620 |
|
16 |
S |
-1.9362 |
-1.9592 |
|
17 |
O |
-1.9907 |
-1.9921 |
|
18 |
O |
-1.6684 |
-1.6817 |
|
19 |
C |
-3.9906 |
-3.9981 |
|
20 |
C |
-3.9876 |
-3.9902 |
|
21 |
C |
-3.9529 |
-3.9556 |
|
22 |
C |
-3.9360 |
-3.9396 |
|
23 |
C |
-3.7991 |
-3.7900 |
|
24 |
C |
-3.1245 |
-3.2028 |
|
25 |
C |
-2.6985 |
-2.6170 |
Table
5: Final energy
evaluation.
|
S.No |
Force
field energy components |
Values
(au) |
|
1 |
Molecular mechanics bond (Estr) |
0.02240327 |
|
2 |
Molecular mechanics angle (Ebend)+
(Estr‑bend) |
0.85887109 |
|
3 |
Molecular mechanics dihedral
(Etor) |
0.02679063 |
|
4 |
Molecular mechanics ImpTor
(Eoop) |
0.00000000 |
|
5 |
Molecular mechanics vdW (EVdW) |
0.05586838 |
|
6 |
Molecular mechanics coulomb (Eqq) |
0.00000000 |
|
Total |
0.96393337
a.u. (604.87786764 kcal/mol) |
|
Among the molecular orbitals,
HOMO (Figure 4) is a non bonding type while the LUMO is a π
molecular orbital. The positive and negative charges are indicated by blue and
red color, respectively. LUMO (Figure 5) map can provide
an idea for nucleophilicity as shown above. The
opaque electrostatic potential (ESP) map (Figure 6) of bicalutamide
exhibits the complete colors for the values of the
ESP energy (in Hartrees) at the points on the
electron density surface. The red color indicates the
increase electron density around the oxygen dominated region of the molecule
representing the most negative regions of the ESP (region of highest stability)
for a positive test charge where it would have favourable interaction energy.
On the other hand the cyano-substituted aromatic ring
of the molecule, shows the region of least stability for the positive test
charge indicating the unfavorable interaction energy.
Thus an ESP-mapped density surface can be used to show the regions of a molecule
that might be more favourable to nucleophilic
or electrophilic attack, making
these types of surfaces useful for the qualitative interpretations [10].
The geometry convergence map of bicalutamide
clearly shows a decrease in potential energy with the progress of circle. The
final SCF energy of bicalutamide was found to be -189.888176 au ( -119156.737100) kcal/mol as
calculated by RHF/PM3 method using ArgusLab 4.0.1
suite. SCF was obtained as the minimum potential energy which is the needed
energy for the interaction of drug with the receptor. The self-consistent field
(SCF) energy is the average interaction between a given particle and other
particles of a quantum-mechanical system consisting of many particles. Beacause the problem of many interacting particles is very
complex and has no exact solution; calculations are done by approximate
methods. One of the most often used approximated methods of quantum mechanics
is based on the interaction of a self-consistent field, which permits the
many-particle problem to be reduced to the problem of a single particle moving
in the average self-consistent field produced by the other particles [13].
It should be noted that the Mulliken charges do not
reproduce the electostatic potentials of a molecule
very well. Mulliken charges were calculed
by determining the electron population of each atom as defined by the basis functions [14].The
standard heat of formation of a compound is the enthalpy change for the
formation of 1 mole of the compound from its constituent elements in their
standard states at 1 atmosphere. Its symbol is ΔHfθ. The most energetically
favourable conformation of bicalutamide was found to
have a heat of formation of 7696.375900
kcal/mol. The steric energy calculated for bicalutamide was 0.963933 a.u.
(604.877867 kcal/mol).
CONCLUSION:
The steric energy was evaluated
in terms of potential energy as a sum of energies associated with bonded interactions (bond length, bond
angle and dihedral angle) as well
as non-bonded interactions (van der Waals and electrostatic).
Surfaces were created to visualize excited state properties such as orbital, electron densities, electrostatic potential (ESP) mapped density. The most energetically favourable
conformation of bicalutamide was found to have a heat of formation of 7696.375900 kcal/mol. The
self-consistent field (SCF) energy
was calculated by geometry convergence function using RHF/PM3 method in ArgusLab
software. The most feasible
position for bicalutamide
to block the androgens receptors on the cells of tissues was found to be -189.8881763568 au
-119156.7371.
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Received on 22.08.2015 Modified on 17.09.2015
Accepted on 02.10.2015
©A&V Publications All right reserved
Res. J. Pharmacognosy & Phytochem.
7(4): Oct-Dec. 2015; Page 214-218
DOI: 10.5958/0975-4385.2015.00032.1