INTRODUCTION:

Dexrazoxane (4,4'-(2S)-propane-1, 2-diyldipiperazine-2,6-dione) a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity^[1]. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines ^[2]. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer ^[3].

As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals ^[4].The exact chelation mechanism is unknown, but it has been postulated that dexrazoxane can be converted into ring-opened form intracellularly and interfere with iron-mediated free radical generation that is in part thought to be responsible for anthryacycline induced cadiomyopathy. It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial drugs ^[5].

Arguslab ^[6] is the electronic structure program that is based on the quantum mechanics; it predicts the potential energies, molecular structure, geometry optimization of structure, vibration frequencies of coordinates of atoms, bond length, bond angles and reaction pathway^[7]. Geometry optimization is fundamental component of molecular modeling. The determination of a low-energy conformation for a given force field can be the final objective of the computation. Alternatively, the minimum for the system on the specified potential energy surface, in a local or globe sense can serve as starting or reference point for subsequent calculation. The energy (E) of molecule is calculated as a sum of terms as in equation 1

E = E _stretching +E _bending +E _torsion +E _Vander
Waals + E _{electrostatic}+ E _{hydrogen bond} + crossterm. (Eqn 1)

These terms are importance for the accurate calculation of geometry properties of molecules. The set of energy functions and the corresponding parameters are called a force field ^[8].

Molecular mechanics method calculates the energy as function of coordinates and energy minimization is an integral part of method. A molecular geometry is constructed by using computer graphics techniques and the atom moved without breaking bonds using an energy minimization technique until the net force on all atoms vanish and the total energy of the molecule reaches a minimum. Structure of molecule corresponding to this energy minimum is one of the stable conformations of the molecule but not necessarily the most stable.

MATERIALS AND METHOD:

The three dimensional quantitative structure activity relationships describe the biological activity of molecule with pharmacological potential as a function of their structural properties^[9,10]. Chemiformatics have generated many tools which are widely used to construct models, minimization and representations of molecular structure ^{[11, 12]}. All conformational analysis (geometry optimization) study was performed on a window based computer using Arguslab ^[6] and ACD Lab ^[13]Chem ketch software’s. Dexrazoxane molecule is utilized to determine 3D structure of molecule. The Dexrazoxane- structure was generated by Arguslab, and minimization was performed with the semi-empirical Austin Model 1 (AM1) parameterization^[14].The minimum potential energy was calculated by using geometry convergence function in Arguslab software. In order to determine the allowed conformation the contact distance between the atoms in adjacent residues is examined using criteria for minimum Vander Waal contact distance^[15]. Surfaces were created to visualize ground state properties as well as excited state properties such as orbital, electron density, electrostatic potentials (ESP) mapped density. The minimum potential energy was also calculated for drug- receptor interaction through the geometry convergence map.

RESULTS AND DISCUSSION:

Prospective view and calculated properties of dexrazoxane molecule is shown in Figure 1. The electron density and active conformation of dexrazoxane by ACDlabs-3D viewer software are shown in Figures 2 and 3 respectively. Figure 4 and 5 shows the highest occupied molecular orbital of molecule (HOMO) and the lowest unoccupied molecular orbital (LUMO) respectively. The positive and negative phases of the orbital are represented by two colors, the blue regions represent a decrease in electron density and the red regions shows increase in electron density. Figure 6 shows electrostatic potential of molecular ground state mapped onto the electron density surface for the ground state. The color map shows the ESP energy (in hartrees) for the various colors. The red end of the spectrum shows regions of highest stability for a positive test charge, magenta/ blue show the regions of least stability for a positive test charge. The self-consistent field (SCF) energy is shown in Figure 7. Atomic coordinates of dexrazoxane molecule is given in Table1. Bond length, bond angles and dihedral angles are given in Tables 2, 3 and 4 respectively, which are calculated after geometry optimization of dexrazoxane molecule from Arguslab by using molecular mechanics calculation. Tables 5 and 6 show the Mulliken atomic charges, ZDO atomic charges and ground state dipole (debye) of dexrazoxane respectively. Table 7 shows calculated energy of dexrazoxane molecule.

Heat of Formation of dexrazoxane was 622.1796 kcal/mol. The steric energy calculated for dexrazoxane was 0.02635060 a.u.(16.53526440 kcal/mol) and SCF energy was found to be -129.1629756809 au (-81051.0640 kcal/mol) as calculated by RHF/ AM1 method, as performed by ArgusLab 4.0.1 suite. The geometry convergence map of dexrazoxane clearly shows a decrease in potential energy with the progress of circle. 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 ^[16]. 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 ^[17].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 ΔH_f^θ.

Figure 1: Prospective view of dexrazoxane by ACD/ChemSketch

Figure 7: SCF energy of dexrazoxane.

Table 1: Atomic coordinates of dexrazoxane.
S.No	Atoms	X	Y		Z
1	C	20.861500	-36.671100		0.000000
2	C	20.861500	-38.001100		0.000000
3	N	19.709600	-36.006100		0.000000
4	N	19.709600	-38.666100		0.000000
5	C	18.557800	-36.671100		0.000000
6	C	18.557800	-38.001100		0.000000
7	C	19.709500	-34.676100		0.000000
8	C	20.861300	-34.011100		0.000000
9	N	20.861300	-32.681100		0.000000
10	C	19.709500	-32.016100		0.000000
11	C	22.013200	-32.016000		0.000000
12	C	19.709500	-30.686000		0.000000
13	C	22.013200	-30.686100		0.000000
14	N	20.861300	-30.021100		0.000000
15	C	22.013200	-34.676100		0.000000
16	O	22.013300	-38.666200		0.000000
17	O	17.406000	-38.666100		0.000000
18	O	23.165000	-30.021100		0.000000
19	O	18.557700	-30.021000		0.000000
20	H	19.709500	-39.996100		0.000000
21	H	20.861300	-28.691100		0.000000
Table 2: Bond length of dexrazoxane
Atoms				Bond length
(C1)-(C2)				1.458000
(C1)-(N3)				1.433804
(C2)-(N4)				1.433804
(C2)-(O16)				1.407689
(N3)-(C5)				1.433804
(N3)-(C7)				1.436817
(N4)-(C6)				1.433804
(N4)-(H20)				1.062577
(C5)-(C6)				1.458000
(C)6-(O17)				1.407689
(C7)-(C8)				1.464000
(C8)-(N9)				1.436817
(C8)-(C15)				1.464000
(N9)-(C10)				1.433804
(N9)-(C11)				1.433804
(C10)-(C12)				1.458000
(C11)-(C13)				1.458000
(C12)-(N14)				1.433804
(C12)-(O19)				1.407689
(C13)-(N14)				1.433804
(C13)-(O18)				1.407689
(N14)-(H21)				1.062577

Table 3: Bond angles of dexrazoxane
Atoms	Bond angles	Alternate angles
(C2)-(C1)-(N3)	120.000000	257.053574
(C1)-(C2)-(N4)	120.000000	257.053574
(C1)-(C2)-(O16)	120.000000	238.736810
(C5)-(N3)-(C1)	120.000000	198.144139
(C1)-(N3)-(C7)	120.000000	197.520556
(N4)-(C2)-(O16)	120.000000	325.928547
(C2)-(N4)-(C6)	120.000000	198.144139
(C2)-(N4)-(H20)	120.000000	108.672864
(C5)-(N3)-(C7)	120.000000	197.520556
(N3)-(C5)-(C6)	120.000000	257.053574
(N3)-(C7)-(C8)	120.000000	254.659028
(C6)-(N4)-(H20)	120.000000	108.672864
(N4)-(C6)-(C5)	120.000000	257.053574
(N4)-(C6)-(O17)	120.000000	325.928547
(C5)-(C6)-(O17)	120.000000	238.736810
(C7)-(C8)-(N9)	120.000000	254.659028
(C7)-(C8)-(C15)	120.000000	186.134654
(N9)-(C8)-(C15)	120.000000	254.659028
(C8)-(N9)-(C10)	120.000000	197.520556
(C8)-(N9)-(C11)	120.000000	197.520556
(C10)-(N9)-(C11)	120.000000	198.144139
(N9)-(C10)-(C12)	120.000000	257.053574
(N9)-(C11)-(C13)	120.000000	257.053574
(C10)-(C12)-(N14)	120.000000	257.053574
(C10)-(C12)-(O19)	120.000000	238.736810
(C11)-(C13)-(N14)	120.000000	257.053574
(C11)-(C13)-(O18)	120.000000	238.736810
(N14)-(C12)-(O19)	120.000000	325.928547
(C12)-(N14)-(C13)	120.000000	198.144139
(C12)-(N14)-(H21)	120.000000	108.672864
(N14)-(C13)-(O18)	120.000000	325.928547
(C13)-(N14)-(H21)	120.000000	108.672864

Table 4: Dihedral angles of dexrazoxane
Atomic Bonds	Dihedral angles
(N4)-(C2)-(C1)-(N3)	5.000000
(O16)-(C2)-(C1)-(N3)	5.000000
(C2)-(C1)-(N3)-(C5)	5.000000
(C2)-(C1)-(N3)-(C7)	5.000000
(C1)-(C2)-(N4)-(C6)	2.500000
(C1)-(C2)-(N4)-(H20)	2.500000
(C1)-(N3)-(C5)-(C6)	5.000000
(C1)-(N3)-(C7)-(C8)	5.000000
(C6)-(N4)-(C2)-(O16)	2.500000
(H20)-(N4)-(C2)-(O16)	2.500000
(C2)-(N4)-(C6)-(C5)	2.500000
(C2)-(N4)-(C6)-(O17)	2.500000
(C6)-(C5)-(N3)-(C7)	5.000000
(C5)-(N3)-(C7)-(C8)	5.000000
(N3)-(C5)-(C6)-(N4)	5.000000
(N3)-(C5)-(C6)-(O17)	5.000000
(N3)-(C7)-(C8)-(N9)	5.000000
(N3)-(C7)-(C8)-(C15)	5.000000
(C5)-(C6)-(N4)-(H20)	2.500000
(O17)-(C6)-(N4)-(H20)	2.500000
(C7)-(C8)-(N9)-(C10)	2.500000
(C7)-(C8)-(N9)-(C11)	2.500000
(C10)-(N9)-(C8)-(C15)	2.500000
(C11)-(N9)-(C8)-(C15)	2.500000
(C8)-(N9)-(C10)-(C12)	5.000000
(C8)-(N9)-(C11)-(C13)	5.000000
(C12)-(C10)-(N9)-(C11)	5.000000
(C10)-(N9)-(C11)-(C13)	5.000000
(N9)-(C10)-(C12)-(N14)	5.000000
(N9)-(C10)-(C12)-(O19)	5.000000
(N9)-(C11)-(C13)-(N14)	5.000000
(N9)-(C11)-(C13)-(O18)	5.000000
(C10)-(C12)-(N14)-(C13)	2.500000
(C10)-(C12)-(N14)-(H21)	2.500000
(C11)-(C13)-(N14)-(C12)	2.500000
(C11)-(C13)-(N14)-(H21)	2.500000
(C13)-(N14)-(C12)-(O19)	2.500000
(H21)-(N14)-(C12)-(O19)	2.500000
(C12)-(N14)-(C13)-(O18)	2.500000
(H21)-(N14)-(C13)-(O18)	2.500000

Table 5: List of Mulliken Atomic Charges and ZDO Atomic Charges of dexrazoxane
S.No	Atoms	ZDO atomic charges	Mulliken atomic charges
1	C	-4.0000	-4.0001
2	C	-4.0000	-4.0000
3	N	-3.0000	-3.0001
4	N	-3.0000	-3.0000
5	C	-4.0000	-4.0000
6	C	-4.0000	-4.0000
7	C	-3.9980	-4.0075
8	C	-2.0232	-2.0096
9	N	4.9847	5.0233
10	C	3.9967	4.0020
11	C	3.9992	4.0028
12	C	3.9913	4.0069
13	C	4.0000	4.0001
14	N	5.0000	5.0000
15	C	-3.9595	-4.0112
16	O	-2.0000	-2.0000
17	O	-2.0000	-2.0000
18	O	6.0000	6.0000
19	O	4.0089	3.9933
20	H	-1.0000	-1.0000
21	H	1.0000	1.0000

Table 6 : Ground State Dipole (debye) of dexrazoxane

Length

172.062699

1153.585589

-0.000000

1166.346982

Table 7: Final steric energy evaluation of dexrazoxane
S.No.	Force field Energy components	Values (au)
1	Molecular mechanics bond (Estr)	0.00171273
2	Molecular mechanics angle (Ebend)+ (Estr‑bend)	0.00171273
3	Molecular mechanics dihedral (Etor)	0.00367445
4	Molecular mechanics ImpTor (Eoop)	0.00000000
5	Molecular mechanics vdW (EVdW)	0.02096342
6	Molecular mechanics coulomb (Eqq)	0.00000000
Total		0.02635060 a.u. (16.53526440 kcal/mol)

CONCLUSION:

The molecular mechanics 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 (Vander Waals and electrostatic). Surfaces were created to visualize excited state properties such as highest occupied molecular orbital’s, lowest unoccupied molecular orbital’s, electron clouds and electrostatic potential (ESP) mapped density. The heat of formation and SCF energy were also evaluated using Arguslab software. The SCF energy represents the most feasible energy where dexrazoxane would bind to the receptor for effective protection against anthracycline-induced cardiac toxicity.

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Received on 24.08.2015 Modified on 10.09.2015

Res. J. Pharmacology & P’dynamics. 7(3): July-Sept., 2015; Page 137-142

DOI: 10.5958/2321-5836.2015.00026.9