Computational Study on
Molecular Orbitals, Excited State Properties and Geometry Optimization of
Anti-benign Prostatic Hyperplasia Drug,
N- (1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide
(Finasteride)
I.E. Otuokere1
and C.O. Alisa2
1Department of Chemistry, Michael Okpara
University of Agriculture, Umudike, Nigeria
2Department of Chemistry, Federal University of Technology, Owerri, Nigeria
*Corresponding Author E-mail: tosmanbaba@yahoo.com
ABSTRACT:
Finasteride,
N-(1,1-dimethylethyl)-3-oxo-(5α,
17β)-4-azaandrost-1-ene-17-carboxamide is a synthetic drug for the
treatment of benign prostatic hyperplasia (BPH) and male pattern baldness
(MPB). The electronic excited-state calculations were carried out by ZINDO
semi-empirical method using ArgusLab 4.0.1 software.
Conformational analysis (geometry optimization) of finasteride
was carried out using PM3 semi-empirical QM parameterization according to Hartree-Fock calculation method by ArgusLab
4.0.1 software. All the results obtained from molecular orbitals, electronic
excited state properties and
electrostatic potential map
suggested the active charged groups in the molecule where interaction with the receptor 5α reductase is probable. The geometry convergence map of finasteride clearly showed a decrease in potential
energy with the progress of rotation. The minimum potential energy was
calculated to be -100315.73 kcal/mol (-159.86 au). The best conformation
of finasteride
was found to be -100315.73
kcal/mol which is the minimum potential
energy calculated by geometry convergence function using ArgusLab
software; performed according to Hartree-Fock
calculation method. The most feasible position for finasteride
to inhibit the receptor 5α reductase was found to be
-100315.73 kcal/mol.
KEYWORDS: Finasteride, ArgusLab 4.0.1 software, benign prostatic hyperplasia,
geometry optimization, potential energy.
INTRODUCTION:
Finasteride,
N-(1,1-dimethylethyl)-3-oxo-(5α,
17β)-4-azaandrost-1-ene-17-carboxamide is a synthetic drug for the
treatment of benign prostatic hyperplasia (BPH) and male pattern baldness
(MPB). It is a type II 5α reductase inhibitor.
5α reductase is an enzyme that converts
testosterone to dihydrotestosterone (DHT)1. Finasteride may
improve the symptoms associated with BPH such as difficulty urinating, getting
up during night to urinate, hesitation at the start of urination and decreased
urinary flow 2. Finasteride is sometimes
used in hormone replacement therapy for male to female transsexuals in
combination with a form of estrogen due to its anti-androgen properties3.
Oral finasteride promotes scalp hair growth and prevents further
hair loss in significant proportions for men with male pattern hair loss 4.
Sexual effects were the most common type of adverse reaction 5,6. The FDA has added a warning to 5α reductase inhibitors concerning an increased risk of
high-grade prostrate cancer 6. The effect
of finasteride on the risk of developing prostrate cancer has not been established, evidence
suggests it may temporarily reduce the growth and prevalence of benign prostrate tumors, but could mask the early detection of prostrate cancer 7. There are case reports of
persistent diminished libido or erectile dysfunction, even after stopping the
drug 8. Mood disorders were not observed as an important adverse
effect in the phase 3 trials leading to regulatory approval of finasteride for the treatment of benign prostatic
hyperplasia (BPH) 9. Nonetheless, a variety of small studies have
suggested a possible connection 10, 11.
Electronic
excitations resulting from energy absorption in the UV/visible region usually
involves changes in the electronic state of a molecule leading to the promotion
of electron from either π bonding or non bonding orbital in ground-state to the π* antibonding
orbital (i.e. π→π* or n→π* transitions respectively) in excited states
11,12. 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 one of the stable
states of lowest energy 13. 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 (van der
Waals and electrostatic) taking place in a molecule and on atomic properties of
a molecule 14. In molecular mechanics, potential energy is
calculated using force field where the atoms move without breaking of bonds
until the energy of the molecule reaches to a minimum also referred as energy
minimization. These minimum energy structures are equilibrium structures
representing minima on the potential energy surface 15.
The present work
describes the computer aided molecular orbitals,
excited state properties and geometry optimization of finasteride
by ArgusLab4.0.1 software.
MATERIALS
AND METHODS:
The electronic
excited-state calculations were carried outby ZINDO
semi-empirical method 17 which is parameterized for low energy
excited-states of organic and organo-metallic
molecules. The structure of
finasteride was drawn and constructed
using window based program of ArgusLab 16
and ACD Lab Chem Sketch software. Conformational
analysis (geometry optimization) of finasteride was
carried out using PM3 semi-empirical QM parameterization 18 according
to Hartree-Fock calculation method by ArgusLab 4.0.1 software 16. Geometry of the
molecule converged after the molecule was drawn and cleaned in ArgusLab. The program computed the energies and cycles.
RESULTS:
The prospective
view, active conformations, Highest Occupied Molecular Orbital, Lowest
Unoccupied Molecular Orbital, electronic excited states, potential energy
geometry convergence graph and
electrostatic potential mapped electron density of finasteride
are presented in Figures 1, 2, 3, 4, 5, 6 and 7 respectively. The geometry
optimized atomic coordinates, bond length, and bond angles of finasteride are presented in Tables 1, 2, and 3
respectively.
Table
1: Atomic Coordinates of Finasteride
|
Atom
Nos |
x |
y |
z |
|
1
C |
7.625600
|
9.997943
|
0.005119 |
|
2
C |
7.625600 |
11.410257
|
0.005119 |
|
3
C |
6.473700
|
9.332943
|
0.162898 |
|
4 N |
6.473700 |
12.075257 |
0.162898 |
|
5
C |
5.321900
|
9.997943
|
0.162898 |
|
6
C |
5.321900 |
11.410257 |
0.162898 |
|
7
C |
9.917175 |
10.060103 |
0.001759 |
|
8
C |
9.929300 |
11.369100
|
0.168017 |
|
9
C |
8.789525
|
9.353097
|
0.334274 |
|
10
C |
8.777400 |
12.034100
|
0.168017 |
|
11
C |
11.069075
|
8.023104
|
0.003574 |
|
12
C |
11.093325
|
9.395096
|
0.003574 |
|
13
C |
9.917175
|
7.400103
|
0.166258 |
|
14
C |
8.789625
|
8.023097
|
0.166258 |
|
15
C |
12.346000
|
7.591101
|
0.162683 |
|
16
C |
13.127800
|
8.751099
|
0.162683 |
|
17
C |
12.346200
|
9.743101
|
0.162683 |
|
18 O |
4.170100 |
12.034100 |
0.000000 |
|
19
C |
7.625500 |
12.699100 |
0.000000 |
|
20
C |
8.715200 |
10.567800 |
0.000000 |
|
21
C |
11.220200 |
10.696800 |
0.000000 |
|
22
C |
7.625600
|
8.709100
|
0.000000 |
|
23
C |
9.929300
|
8.709100
|
0.000000 |
|
24
C |
11.220200
|
6.721400
|
0.000000 |
|
25
C |
12.757100
|
6.368200
|
0.000000 |
|
26
N |
14.058000 |
6.091700
|
0.000000 |
|
27
O |
11.867100
|
5.379800
|
0.000000 |
|
28
C |
14.947900
|
7.080100
|
0.000000 |
|
29
C |
16.248900
|
6.803700
|
0.000000 |
|
30
C |
14.536900
|
8.345000
|
0.000000 |
|
31
C |
15.359000
|
5.815300
|
0.000000 |
Table
2: Bond lengths of Finasteride
|
Atom
Numbers |
Bond Lengths |
Alternate
Bond Lengths |
||
|
1
3 |
(C) |
(C) |
1.489000 |
367.716672 |
|
1
9 |
(C) |
(C) |
1.514000 |
349.799987 |
|
1
2 |
(C) |
(C) |
1.514000 |
349.799987 |
|
1
22 |
(C) |
(C) |
1.489000 |
367.716672 |
|
2
4 |
(C) |
(N) |
1.447870 |
532.154321 |
|
2
10 |
(C) |
(C) |
1.489000 |
367.716672 |
|
2
19 |
(C) |
(C) |
1.489000 |
367.716672 |
|
3
5 |
(C) |
(C) |
1.328833 |
517.352113 |
|
4
6 |
(N) |
(C) |
1.422764 |
560.825517 |
|
5
6 |
(C) |
(C) |
1.464000 |
386.878134 |
|
6
18 |
(C) |
(O) |
1.410739 |
520.112242 |
|
7
8 |
(C) |
(C) |
1.489000 |
367.716672 |
|
7
12 |
(C) |
(C) |
1.514000 |
349.799987 |
|
7
9 |
(C) |
(C) |
1.514000 |
349.799987 |
|
7
23 |
(C) |
(C) |
1.489000 |
367.716672 |
|
8
10 |
(C) |
(C) |
1.464000 |
386.878134 |
|
9
14 |
(C) |
(C) |
1.489000 |
367.716672 |
|
9
20 |
(C) |
(C) |
1.463000 |
387.672001 |
|
11
13 |
(C) |
(C) |
1.489000 |
367.716672 |
|
11
15 |
(C) |
(C) |
1.489000 |
367.716672 |
|
11
12 |
(C) |
(C) |
1.514000 |
349.799987 |
|
11
24 |
(C) |
(C) |
1.489000 |
367.716672 |
|
12
17 |
(C) |
(C) |
1.489000 |
367.716672 |
|
12
21 |
(C) |
(C) |
1.489000 |
367.716672 |
|
13
14 |
(C) |
(C) |
1.464000 |
386.878134 |
|
15
16 |
(C) |
(C) |
1.464000 |
386.878134 |
|
15
25 |
(C) |
(C) |
1.464000 |
386.878134 |
|
16
17 |
(C) |
(C) |
1.464000 |
386.878134 |
|
25
26 |
(C) |
(N) |
1.346235 |
662.009133 |
|
25
27 |
(C) |
(O) |
1.260307 |
729.470867 |
|
26
28 |
(N) |
(C) |
1.447870 |
532.154321 |
|
28
29 |
(C) |
(C) |
1.489000 |
367.716672 |
|
28
30 |
(C) |
(C) |
1.489000 |
367.716672 |
|
28
31 |
(C) |
(C) |
1.489000 |
367.716672 |
Table
3: Bond Angles of Finasteride
|
Atom
Numbers |
Bond
Angles |
Alternate
Bond Angles |
|||
|
3
1 9 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
3
1 2 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
3
1 22 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
1
3 5 |
(C) |
(C) |
(C) |
120.000000 |
207.955672 |
|
9
1 2 |
(C) |
(C) |
(C) |
109.470000 |
214.211821 |
|
9
1 22 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
1
9 7 |
(C) |
(C) |
(C) |
109.470000 |
214.211821 |
|
1
9 14 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
1
9 20 |
(C) |
(C) |
(C) |
109.470000 |
225.286699 |
|
2
1 22 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
1
2 4 |
(C) |
(C) |
(N) |
109.470000 |
304.253928 |
|
1
2 10 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
1
2 19 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
4
2 10 |
(N) |
(C) |
(C) |
109.470000 |
312.267092 |
|
4
2 19 |
(N) |
(C) |
(C) |
109.470000 |
312.267092 |
|
2
4 6 |
(C) |
(N) |
(C) |
120.000000 |
197.498361 |
|
10
2 19 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
2
10 8 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
3
5 6 |
(C) |
(C) |
(C) |
120.000000 |
213.837163 |
|
4
6 5 |
(N) |
(C) |
(C) |
120.000000 |
258.357159 |
|
4
6 18 |
(N) |
(C) |
(O) |
120.000000 |
328.721534 |
|
5
6 18 |
(C) |
(C) |
(O) |
120.000000 |
236.478255 |
|
8
7 12 |
C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
8
7 9 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
8
7 23 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
7
8 10 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
12
7 9 |
(C) |
(C) |
(C) |
109.470000 |
214.211821 |
|
12
7 23 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
7
12 11 |
(C) |
(C) |
(C) |
109.470000 |
214.211821 |
|
7
12 17 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
7
12 21 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
9
7 23 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
7
9 14 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
7
9 20 |
(C) |
(C) |
(C) |
109.470000 |
225.286699 |
|
14
9 20 |
(C) |
(C) |
(C) |
109.470000 |
231.152617 |
|
9
14 13 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
13
11 15 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
13
11 12 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
13
11 24 |
(C) |
(C) |
(C) |
109.470000 |
225.18377 |
|
11
13 14 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
15
11 12 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
15
11 24 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
11
15 16 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
11
15 25 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
12
11 24 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
11
12 17 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
11
12 21 |
(C) |
(C) |
(C) |
109.470000 |
219.577891 |
|
17
12 21 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
12
17 16 |
(C) |
(C) |
(C) |
120.000000 |
181.430228 |
|
16
15 25 |
(C) |
(C) |
(C) |
120.000000 |
186.134654 |
|
15
16 17 |
(C) |
(C) |
(C) |
120.000000 |
186.134654 |
|
15
25 26 |
(C) |
(C) |
(N) |
120.000000 |
279.479738 |
|
15
25 27 |
(C) |
(C) |
(O) |
120.000000 |
275.966448 |
|
26
25 27 |
(N) |
(C) |
(O) |
120.000000 |
421.698151 |
|
25
26 28 |
(C) |
(N) |
(C) |
120.000000 |
213.828263 |
|
26
28 29 |
(N) |
(C) |
(C) |
109.470000 |
312.267092 |
|
26
28 30 |
(N) |
(C) |
(C) |
109.470000 |
312.267092 |
|
26
28 31 |
(N) |
(C) |
(C) |
109.470000 |
312.267092 |
|
29
28 30 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
29
28 31 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
|
30
28 31 |
(C) |
(C) |
(C) |
109.470000 |
225.183707 |
DISCUSSIONS:
The Highest
Occupied Molecular Orbital, HOMO (Figure
3) is a non bonding type that is in the plane of the molecule while the Lowest
Unoccupied Molecular Orbitals, LUMO (Figure 4) is a
π molecular orbital perpendicular to the plane of the molecule. The
positive and negative charges are indicated by blue and red color,
respectively.
The UV/visible
electronic absorption spectrum of finasteride is shown in Figure 5. The spectrum showed intense peak at
324 nm, while relatively low intensity peaks appeared at 250, 270 and 700 nm
representing the strength of transitions of the compound. These transitions
have been assigned i.e. π→π*, π→π*, π→π* and n→π*
transitions respectively 19.
The geometry
convergence map of finasteride (Figure 6), clearly
showed a decrease in potential energy with the progress of rotation. The
minimum potential energy was calculated to be
-100315.73 kcal/mol
(-159.86 au). The best conformation of finasteride was
found to be -100315.73 kcal/mol which is the minimum potential energy
calculated by geometry convergence function using ArgusLab
software; performed according to Hartree-Fock
calculation method. The most feasible position for finasteride
to inhibit the receptor 5α reductase was found to be
-100315.73 kcal/mol. The geometry optimized atomic coordinates, bond lengths
and bond angles of finasteride have been presented in
Tables 1, 2, and 3 respectively.
ArgusLab
software generated mapped surface of finasteride
(Figure 7). The electrostatic potential (ESP) was mapped onto the surface
of the electron density. In the ESP-mapped density surface, the electron
density surface gave the shape of the surface while the value of the ESP on
that surface gave the colors 16. The electrostatic potential
is the potential energy felt by a positive "test" charge at a
particular point in space. The colors are the values of the ESP energy (in Hartrees) at the points on the electron density surface.
The red color indicated the enhanced electron density representing the most
negative regions of the ESP (region of highest stability) for a positive test
charge where it would have favorable interaction energy. On the other hand the
magenta/blue color, showed 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.
All the results
obtained from molecular orbitals, electronic excited
state properties and electrostatic potential
map represent the active sites with
charged groups of the molecule where interaction with the receptor, 5α reductase is probable. Such calculations are applicable in
determining reaction mechanisms, conducting spectroscopic analysis and in the
understanding of the excited-state phenomena 11. Results of the
geometry convergence map showed the most feasible position for finasteride to inhibit the receptor 5α reductase.
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.
Received on 01.11.2014 Accepted on 25.11.2014
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Asian J. Res.
Pharm. Sci. 4(4): Oct.-Dec.
2014; Page 169-173