Introduction
Lisinopril is a drug of the angiotensin-converting
enzyme (ACE) inhibitor class used primarily in treatment of hypertension, congestive heart
failure,
and heart attacks, and also in
preventing renal and retinal complications of diabetes. Its indications, contraindications and side effects are as those for all ACE inhibitors1. Angiotensin
converting enzyme inhibitors (ACE-I) have been found generally to have neutral
or even favorable effects on glucose metabolism and on insulin sensitivity in
both non diabetic2-4 and diabetic hypertensive patients5-7.
Lisinopril was the third ACE inhibitor (after captopril and enalapril) and was
introduced into therapy in the early 1990s8. A number of properties
distinguish it from other ACE inhibitors: It is hydrophilic, has a long half-life and tissue penetration, and is not metabolized by the liver9. Lisinopril causes the kidneys to retain potassium, which
may lead to hyperkalemia9. Lisinopril has
been assigned to pregnancy category D by the FDA for use during the second and
third trimesters and to category C during the first trimester10.
Animal and human data
have revealed evidence of embryolethality and teratogenicity associated with angiotensin-converting
enzyme (ACE) inhibitors10. There are no controlled data in human
pregnancy. Congenital malformations have been reported with the use of ACE
inhibitors during the first trimester of pregnancy, while fetal and neonatal toxicity,
death, and congenital anomalies have been reported with their use during the
second and third trimesters of pregnancy10. If the patient becomes
pregnant, lisinopril should be discontinued as soon
as possible; it is considered contraindicated during pregnancy. There are no
data on the excretion of lisinopril into human milk.
The manufacturer recommends, due to the potential for serious adverse reactions
in nursing infants, a decision should be made to discontinue nursing or
discontinue the drug, taking into account the importance of the drug to the
mother10. Lisinopril is the lysine-analog of enalapril. Unlike other ACE
inhibitors, it is not a prodrug and is excreted
unchanged in the urine. In cases of overdosage, it
can be removed from circulation by dialysis11
Argus Lab12 is the electronic structure
program that is based on the quantum mechanics, it predicts the potential
energies,
molecular structures; geometry optimization of structure, vibration frequencies
of coordinates of atoms,
bond
length, bond angle and reactions pathway 13. The molecular mechanics
method calculates the energy as the function of the coordinates and energy.
Energy minimization is an intergral part of the
method14. The basic functional form of a force field (potential
energy) encapsulates both bonded terms relating to atoms that are linked by covalent bonds, and nonbonded (also called
"noncovalent") terms describing the
long-range electrostatic and van der Waals
forces. The specific decomposition of the terms depends on the force field 15,
16, 17, 18, but a general form for the total energy in an additive force
field can be written as
The components of the
covalent and noncovalent contributions are given by the following
summations:
3
The bond and angle
terms are usually modeled as harmonic
oscillators in force fields that do not allow bond breaking. The functional form
for the rest of the bonded terms is highly variable15, 16, 17, and 18.
Proper dihedral potentials are usually included. Additionally, "improper torsional" terms may be added to enforce the planarity
of aromatic rings and other conjugated systems, and "cross-terms" that describe
coupling of different internal variables, such as angles and bond lengths. Some
force fields also include explicit terms for hydrogen bonds15- 18.
In this research, we
present the molecular mechanics
potential energy function of Angiotensin-Converting Enzyme (ACE) inhibitor, Lisinopril.
MATERIALS AND METHODS:
All conformational analysis (geometry optimization) study
was performed on a window based computer using Argus lab 4.0.1 and ACD Lab Chem Sketch software . Lisinopril structure was sketched with ACD Lab Chem Sketch software and saved as MDL Molfiles(*mol). The lisinopril
structure was generated by Argus lab, and minimization was performed with the
semi-empirical Austin Model 1 (AM1) parameterization 19. The minimum
potential energy is calculated by using geometry convergence function in Argus
lab software.
RESULTS:
The Prospective view,
active conformation, electrostatic potential, Highest Occupied Molecular Orbitals of Lisinopril (HOMO) and
Lowest Unoccupied Molecular Orbitals of Lisinopril (LUMO) are presented in Figures 1 5 respectively. The atom coordinates,
bond length, bond angles, dihedral angles, improper torsions and final potential
energy evaluation are presented in Tables 1 6 respectively.
DISCUSSIONS:
ArgusLab generated mapped
surface of lisinopril (Figure 3). 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 12. The electrostatic potential is the potential
energy felt by a positive "test" charge at a particular point in
space 12. . Thus, the ESP-mapped density surface showed
regions of lisinopril that might be more favorable to
nucleophilic or electrophilic
attack, making these types of surfaces useful for qualitative interpretations
of chemical reactivity. Another way to think of ESP-mapped density
surface of the lisinopril is that it showed
"where" the frontier electron density for the molecule is greatest
(or least) relative to the nuclei 12. The red region showed the
greatest increase in electron density centered over the carbon (the ESP
difference is negative indicating that the ESP became more negative as electron
density increased in this region). Also, the magenta region showed the
greatest decrease in electron density (since electron density decreased, the
ESP became more positive). The various other colors showed how ESP
difference changes on all points of the electron density surface.
The highest occupied molecular
orbital (HOMO) of lisinopril (Figure 4) is a
non-bonding type MO that is in the plane of the molecule. The lowest
unoccupied molecular orbital (LUMO) (Figure 5) is a π MO perpendicular to
the plane of the molecule. The first excited state of lisinopril
is an n→π* transition that is
composed almost exclusively of the HOMO → LUMO transition.The
HOMO is localized to the plane of the molecule and is a non-bonding MO.
The LUMO is perpendicular to the plane of the molecule and is a combination of
the pz atomic orbitals.
Atom coordinates of Lisinopril (Table 1) is the lowest energy conformation of
the molecule. Arguslab system made several changes in
the atom position through rotation. The molecule was geometrically optimized. This
process is termed energy minimization. This is the main objective of molecular
mechanic The geometry optimized bond lengths have been
presented in Figure 2. The molecular mechanics bond length energy (Table 6) was
calculatedd to be 0.00573278 au. The bond length
energy was calculated based on equation 4 5, 16-18.
Kb is the
force constant of lisinopril, evaluated from quantum
mechanics. The parameters b and bo
are the bond length and ideal bond length of lisinopril.
The molecular
mechanics bond angle energy (Table 6) was found to be 0.05431651 au. This
energy was associated with summation of the alterations of bond angles, 
from ideal values o, multiplied by the
force constant Ko
as presented in equation 55, 16-18.
The potential energy
of the dihedral angle and improper torsions were simulated based on Equation 65,
16-18. The potentials were assumed to be periodic and expressed as cosine
function. The value of the dihedral energy and improper torsions are 0.03526854
and 0.00116311 au respectively.
The energy term representing the contribution
of non-bonded interactions in the potential function of lisinopril
had two components, the Vander Waals interaction energy and the electrostatic
interaction energy. In the Potential function these interactions accounted for
the electrostatic and Vander Waals interactions. The Vander Waals interactions
between two atoms of lisinopril aroused from a
balance between repulsive and attractive forces. The repulsive forces emanated
at short distances where the electron electron interaction is strong. The
attractive forces, also referred to as the dispersion force aroused from
fluctuations in the charge distribution of the electron cloud. The fluctuation
in the electron distribution on the atom gave rise to an instantaneous dipole
which in turn induced a dipole in a second atom which gave rise to attractive
interactions. The Vaander Waals interaction could
also be modeled using Lennard-Jones 612 potential (Equation
7)5,16-18 which expressed the interaction energy using the atom-type
dependent constant, A and C. Values of A and C were determined by non-bonding
distances in lisinopril while r and K represent the
atomic separation and force constant respectively. The Van-der-Waals
potential energy was simulated to be 0.0289863 au.
The final molecular mechanics potential energy function of lisinopril was simulated to be 0.12546697 a.u (78.73178401 Kcal/mol). Conformational analyses (Geometry
optimization) of nucleosidic antitumor antibiotic showdomycin by Arguslab 4
Software have been reported 20. The
minimum potential energy was calculated by geometry convergence function. It
was discovered that the most feasible position for the drug to interact with
the receptor was −0.269696 K.cal/mole. We hereby suggest that the most
feasible potential energy for lisinopril to act as angiotensin-converting enzyme (ACE) inhibitor is 78.73178401 Kcal/mol
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