JOURNAL OF MULTIFUNCTIONAL MATERIALS & PHOTOSCIENCE
7(2), December 2016, pp. 111-117
Halla T. Mohammed, and Abbas A-Ali Drea
Chemistry Department, College of Science, Babylon University, Hilla, IRAQ
Abstract: Simulation studies of nine compounds have been suggested to treat Parkinson’s disease
using quantum calculation methods. Geometrical properties and vibration spectra have been
calculated for all suggested chemical compounds to estimate the best for Parkinson’s disease
treatment by calculating the potential energy surface, atomic charge, bond length, bond angle,
dipole moment, electrostatic potential and molecular orbital energy with energy gap. The
calculations show that the M-6-SPhe compound has the structure and chemical properties of
an ideal value compared to other suggested chemical compounds. Also, it has the lowest value
of dipole moment equal to 3.028 Debye, and it has the highest value of the energy gap equal to
8.786 eV compared to the other chemical compounds suggested.
Keywords: Semi-empirical method, DFT, Parkinson’s disease, Prodrug.
INTRODUCTION
Studies have proven Parkinson’s disease PD was widespread more than 4 million people
worldwide suffer from Parkinson’s. The number of cases was rising where about 50,000
new cases are recorded each year[1]. This disease was considered the second most common
neurodegenerative disease after Alzheimer’s disease. This disease causes, tremor,
bradykinesia (slowed movement), and rigidity. The risk of this disease is the process of
PD in your body may start 5 to 20 years before the first symptoms are recognized[2]. The
symptoms of PD result from the die or weakness of the substantianigra (literally “black
substance”). Usually, these cells produce a chemical messenger called Dopamine, which
transmits signals inside the brain to produce smooth and easy physical movements[3,4].
The most effective treatment for PD is give a modified amino acid known as L-DOPA,
which is converted to dopamine in the brain. L-dopa (3, 4-dihydroxy-L-phenylalanine) is
a chemical compound synthesis in the human body made from L-Tyrosine, in some cases
from L-phenylalanine. L-DOPA, a dopamine precursor, either alone or in combination
with an aromatic amino acid decarboxylase inhibitor (carbidopa, benserazide) is the most
effective drug for the treatment of PD, because they able to cross the blood-brain barrier,
whereas Dopamine itself cannot [5-8].
*Corresponding author: aadreab22@yahoo.com
Most symptomatic medications used in the treatment are: Levodopa, Dopamine
agonists, MAO-B inhibitors, Amantadine, Anticholinergic, and COMT-inhibitors. These
current treatments only reduce the symptoms of the PD for a limited period, most of these
drugs preparing as a prodrugs [9]. Prodrug is a very versatile strategy to increase the
Interest of biologically active compounds and decrease their associated toxicity. First
described by Adrien Albert in the late 1958 [10]. It is a medication or compound which
inactive, but which can be transformed by enzymatic to release the active parent drug in
the human body. The aim of prodrug manufacturing through chemically modified
derivatives of active drug compounds to hide unwanted drug properties, like low solubility
in lipid or water, low selectivity, chemical instability, toxicity, to reduce side effects, and
to enhance the absorption, distribution [11-13].
The present study tends to treat for Parkinson’s disease. Different prodrugswere
suggested to find the best prodrug to treat Parkinson’s disease theoretically through the
quantum calculationprocesses of the electronic and geometrical structure by using PM3
of semi-empirical calculations and DFT minimal STO-3G.
COMPUTATIONAL DETAILS
Theoretical calculations were completed by using the computational implemented in the
Hyperchem Version 8.0.9 program [14-15]. Geometry optimization, electronic energies,
heat of formation for diffrentprodrugs suggested have been optimized at semi empirical
method and DFT- STO-3G. The highest occupied molecular orbital (HOMO) and the lowest
unoccupied molecular orbital (LUMO) were studied to calculate the energy gap (?E) [16,
17]. Bond lengths, bond angle, and the charge of atoms have been calculated at semiempirical
method, PM3 level [18].
RESULTS AND DISCUSSION
Several prodrugs of medication treatment for Parkinson’s disease have been suggested
and study the geometrical structure of all prodrugs. Where, sugar molecules include
fructose, glucose, and mannose were linked to the amino group of the Phenylaniline linked
to a different position (C1, C3, and C6) of the sugar through succinyl linker, to be lipophilic
derivatives of Phenylaniline in order to transfer through the blood-brain barrier, which
have selective permeability [19]. Fig. 1 represent the geometrical structure of suggested
prodrug.
The energies of bond stability of different prodrug calculated by a semi empirical
PM3 method and shown in Table 1. From Table 1 note that N-C2 4 bond in M-3-SPhe, M-
6-SPhe, and F-3-SPhe molecules are more stable than in other probable drug due to require
80.1, 79.8, and 80 kCal/mol respectively of bond dissociation energy.
Potential energy stability of N-C2 4-O2 angle of all prodrugs were calculated, and
represented in Table 2. From Table 1 note that N-C2 4-O2 angle in the M-6-SPhe molecule
was requires 2950 kCal/mol higher value dissociation energy than other prodrogs. So
this angle is more stability in M-6-SPhe than in other prodrugs.
Figure 1: Chemical structure of suggested prodrugs
Table 1: Potential energy stability and dissociation of N-C2 4
bond length calculate at semi
empirical PM3 method
Table 3 represents energetic properties of proposed prodrugs. M-6-SPhe has -132291.816
kCal/mol total energy less energy than other prodrugs, so it considers favorite[20[, and it
has -400.534 kCal/mol heat of formation, That means this formation reaction from initial
elements is exothermic, so it needs the amount of energy in order to decompose to the
initial elements. This means that the M-6-SPhe compound is more stable than other
probable[21]. HOMO energy for highest occupied molecular orbital, it shows the ability
the molecule to the loss of electrons, since whenever the value was higher became easy to
loss the electrons in the pharmaceutical compounds, While LUMO energy for lowest
unoccupied molecular orbital, it shows the ability the molecule to acquire electrons, since
whenever the value was less became easy to acquire electrons[22]. Therefore the compound
has the highest value of the energy gap is the most effective in the pharmaceutical
compounds. The M-6-SPhe compound has 8.786 eV energy gap higher than other probable.
HOMO, and LUMO are show at two and three dimensions in Fig 2.The M-6-SPhe
compound has the lowest value of dipole moment equal to 3.028 Debye, So become more
lipophilic than other prodrugs.
Table 2
Potential energy stability of N-C2 4=O2 bond angle calculates at semi empirical PM3 method
Table 3
The properties of energy for all pordrugs calculated by a semi empirical PM3 method
Energy properties of the most stability compound M-6-SPhe calculated by DFT- STO-
3G level of theory and semi empirical PM3 method and listed in Table 4. From Table 3-8
notice there are different in a value between tow method, because DFT method more
accurate than semi empirical methods. The semi empirical method depends on empirical
values and neglect of a large number of electron integrals. However, it was considered an
important method due to require a short time for calculation. Also, it was able to calculate
heat formation, while DFT it self cannot [23].
Chemical effectiveness of M-6-SPhe has been studied include electronic potential, total
charge density is shown in Fig 3. Fig 3 shows that the regions of high electron density on
the oxygen atom of the red color, while regions with low electron density of the atoms of
hydrogen represented green color. The electronic density centered on the oxygen and
nitrogen atoms because they contain a loan pair, also notes that the hydrogen atoms are
suffer decrease electronic density due to high electrostatic of nitrogen and oxygen[24].
Figure 2: HOMO and LUMO levels of M-6-SPhe
CONCLUSION
The M-6-SPhe prodrug is better than other suggested prodrugs due to: The
relaxation energy value of the geometrical optimization structure is less than
other suggested structures. It has the highest value of the energy gap, so it is the
most stable in the pharmaceutical compounds.It has the lowest value of the dipole
moment, so become more lipophilic than other prodrugs to be able to cross the bloodbrain
barrier.
Table 4
Energy properties of M-6-SPhe calculated by DFT- STO-3G level of theory and semi
empirical PM3 methods
DFT Semi empirical PM3
Total energy (kCal/mol) -339169.320 -132291.816
ZPE kCal/mol) 335.188 273.472
Heat of Formation - -400.534
kCal/mol
Molecular HOMO -7.629 -10.067
orbital energy (eV)
LUMO 1.538 -0.241
(eV)
?Egab 9.167 8.786
(eV)
Dipole moment 2.630 3.028
Time of calculation 739:11:36 0:11:25
(hours)
Figure 3: Physical properties of geometry optimization M-6-SPhe calculated at semi empirical method
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