Conformational analysis and excited – state properties of a highly potent and totally selective aromatase inhibitor,

4,4'-(1H-1,2,4-triazol-1-ylmethanediyl) dibenzo nitrile (letrozole)

 

 I.E. Otuokere, F. J. Amaku

 Department of Chemistry, Michael Okpara University of Agriculture, Umudike, Nigeria.                                     

*Corresponding Author E-mail: ifeanyiotuokere@gmail.com

 

ABSTRACT:

4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile (letrozole) is a highly potent and totally selective aromatase inhibitor used in treatment of early breast cancer in women who have experienced menopause (end of monthly menstrual periods) and who have had other treatments, such as radiation or surgery to remove the tumor. Conformational analysis  studies of letrozole were based on Arguslab software. The molecular mechanics potential energy function wer evaluated in terms 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 and electrostatic potential (ESP) mapped density. The steric energy for letrozole was calculated to be 0.116739 a.u. (73.255075 kcal/mol). The most energetically favourable conformation of letrozole was found to have a heat of formation of 1208.5864 kcal/mol. The self-consistent field (SCF) energy was calculated by geometry convergence function using RHF/AM1 method with a net charge of -1 and valence electron of 94 , in ArgusLab software. The most feasible position for letrozole  to  act as a highly potent and totally selective aromatase inhibitor  was found to be -116.271466 au (-72961.512600 kcal/mol)

 

KEYWORDS: Arguslab, letrozole, molecular mechanics, conformation analysis, aromatase inhibitor.

 

 

INTRODUCTION:

4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile, letrozole is used treat early breast cancer in women who have experienced menopause (end of monthly menstrual periods) and who have had other treatments, such as radiation or surgery to remove the tumor [1,2]. It is also used to treat early breast cancer in women who have experienced menopause and who have already been treated with a medication called tamoxifen (Nolvadex) for 5 years. Letrozole is also used in women who have experienced menopause as a first treatment of breast cancer that has spread within the breast or to other areas of the body or in women whose breast cancer has worsened while they were taking tamoxifen. Letrozole is in a class of medications called nonsteroidal aromatase inhibitors [3].

 

It works by decreasing the amount of estrogen produced by the body. This can slow or stop the growth of some types of breast cancer cells that need estrogen to grow.Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition [4,5] .  Modern third-generation aromatase inhibitors effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole achieved the goal of discovering a highly potent and totally selective aromatase inhibitor [6]. 

 

The energies computed by molecular mechanics are usually conformational energies. This means that the energy computed is meant to be an energy that will reliably predict the diference in energy from one conformation to the next. The effect of strained bond lengths or angles is also included in this energy. This is not the same as the total energies obtained from ab initio programs or the heat of formation from semiempirical programs. Molecular mechanics methods are not generally applicable to structures very far from equilibrium, such as transition structures. Arguslab [9] 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 [7]. Conformational analysis of molecule is based on molecular mechanics, it is a method for the calculation of molecular structures, conformational energies and other molecular properties using concept from classical mechanics. The energy (E) of the molecule is calculated as a sum of terms as in equation (1).

 

E = Estretching + Ebending + Etorsion + EVander Waals + Eelectrostatic + Ehydrogen bond + cross term  (Equation 1)

 

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

 

We hereby present, in silico conformational analysis and excited – state properties of a highly potent and totally selective aromatase inhibitor , 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzo nitrile(letrozole).

 

MATERIALS AND METHOD:

The structure of 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl) dibenzonitrile (letrozole)  was drawn and constructed using window based program of Arguslab [9] and ACDl ab ChemSketch [10] software. Conformational analysis (geometry optimization) of letrozole was carried out using PM3 semi-empirical QM parameterization according to Hartree-Fock calculation method by ArgusLab 4.0.1 software. Geometry of the molecule was converged after the molecule was drawn and cleaned in Arguslab and the program computed the energy until the maximum cycles reached for the convergence (stopping point) of the molecule. 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/AM1 method, as performed by Arguslab 4.0.1 suite.

 

RESULTS AND DISCUSSION:

Atomic coordinates of letrozole molecule is given in Table1. Bond length and bond angles are given in Tables 2 and 3, respectively, which are calculated after geometry optimization of letrozole molecule from Arguslab by using molecular mechanics calculation. Tables 4 and 5 show the Mulliken atomic charges, ZDO atomic charges of letrozole and the calculated steric energy of letrozole molecule. Prospective view and calculated properties of Letrozole molecule is shown in Figure1. The electron cloud density mapped and active conformation of letrozole by ACDlabs-3D viewer software is shown in Figures 2 and 3 respectively. Figures 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 an decrease in electron density and the red regions shows a increase in electron density.  Figure 6 shows electrostatic potential of molecular ground state mapped onto the electron density surface. 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 SCF convergence energy map of letrozole is reported in Figure 7.

 

Heat of formation of 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile (letrozole)  was  1208.5864 kcal/mol. 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 steric energy calculated for letrozole was 0.11673929 a.u. (73.25507545 kcal/mol)  and SCF energy was found to be -116.2714665257 au (-72961.5126 kcal/mol) as calculated by RHF/AM1 method with a net charge of -1 and valence electron of 94 , as performed by 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 [11].

 

 

Figure 1: Prospective view of Letrozole by ACD/ChemSketch

 

Figure 2: Electron density clouds of Letrozole by ACDlabs. 3D viewer.

 

 

Figure 3: Prospective view of active conformation of Letrozole by Arguslab.

 

Figure 4: Highest occupied molecular orbital’s (HOMO) of Letrozole.

 

Figure 5: Lowest unoccupied molecular orbital’s (LUMO) of Letrozole.

 

Figure 6: Electrostatic potential mapped density of Letrozole.

 

 

Figure 7: SCF energy of Letrozole.

 

Table 1: Atomic coordinates of  letrozole.

Atoms

X

Y

Z

1  

C

   21.903000

 -16.496800

   0.000000

2 

C

   21.903000

 -17.826800

   0.000000

3

C

   20.751100 

 -15.831800  

   0.000000

4

C

   20.751100

 -18.491800

   0.000000

5

C

  19.599400

 -16.496800

   0.000000

6

C

  19.599400

 -17.826800

   0.000000

7

C

   20.751100

 -19.821800

   0.000000

8

C

   20.751100

 -14.501800

   0.000000

9

C

   21.902900

 -13.836800

   0.000000

10

C

   24.206600

 -12.506800

   0.000000

11

C

   24.206600

 -13.836800

   0.000000

12

C

   23.054700

 -11.841800

   0.000000

13

C

   23.054700

 -14.501800

   0.000000

14

C

   21.902900

 -12.506800

   0.000000

15

N

   19.599300

 -13.836800

   0.000000

16

N     

    17.859200

   -12.570400

   0.000000

17

C

   18.935900

 -11.789600

   0.000000

18

C

   18.269100

 -13.835700

   0.000000

19

N

   20.011200

 -12.572300

   0.000000

20

N

   19.599300

 -20.486800

   0.000000

21

C

   25.358400

 -11.841800

   0.000000

22

N

   26.510200

 -12.506800

   0.000000

 

Table 2: Bond length of letrozole

Atoms

     Bond length

(C1)-(C2)

     1.458000 

(C1)-(C3)

     1.323387

(C2)-(C4)

     1.323387 

(C3)-(C5)

     1.458000 

(C3)-(C8)

     1.461000 

(C4)-(C6)

     1.458000 

(C4)-(C7)

     1.461000 

(C5)-(C6)

     1.323387 

(C7)-(N20)

     1.437821 

(C8)-(C9)

     1.461000 

(C8)-(N15)

     1.436817

(C9)-(C13)

     1.323387 

(C9)-(C14)

     1.458000 

(C10)-(C11)

     1.323387 

(C10)-(C12)

     1.458000 

(C10)-(C21)

     1.461000 

(C11)-(C13)

     1.458000 

(C12)-(C14)

     1.323387

(N15)-(C18)

     1.433804 

(N15)-(N19)

     1.398000 

(N16)-(C17)

     1.433804

(N16)-(C18)

     1.301961

(C17)-(N19)

     1.301961 

(C21)-(N22)

     1.437821

 

Table 3: Bond angles of  letrozole

Atoms

Bond angles

Alternate angles

(C2)-(C1)-(C3)

 120.000000

 216.488007

(C1)-(C2)-(C4)

 120.000000

 216.488007

(C1)-(C3)-(C5)

 120.000000

 216.488007

(C1)-(C3)-(C8)

 120.000000

 215.760874

(C2)-(C4)-(C6)

 120.000000

 216.488007

(C2)-(C3)-(C7)

 120.000000

 215.760874

(C5)-(C3)-(C8)

 120.000000

 187.861407

(C3)-(C5)-(C6)

 120.000000

 216.488007

(C3)-(C8)-(C9)

 120.000000

 187.283630

(C3)-(C8)-(N15)

 120.000000

 255.456798

(C6)-(C4)-(C7)

 120.000000

 187.861407

(C4)-(C6)-(C5)

 120.000000

 216.488007

(C4)-(C7)-(N20)

 120.000000

 255.193425

(C9)-(8C)-(N15)

 120.000000

 255.456798

(C8)-(C9)-(C13)

 120.000000

 215.760874

(C8)-(C9)-(C14)

 120.000000

 187.861407

(C8)-(N15)-(C18)

 120.000000

 197.520556

(C19)-(N15)-(N8)

 120.000000

 272.827854

(C13)-(C9)-(C14)

 120.000000

 216.488007

(C9)-(C13)-(C11)

 120.000000

 216.488007

(C9)-(C14)-(C12)

 120.000000

 216.488007

(C11)-(C10)-(C12)

 120.000000

 216.488007

(C11)-(C10)-(C21)

 120.000000

 215.760874

(C10)-(C11)-(C13)

 120.000000

 216.488007

(C12)-(C10)-(C21)

 120.000000

 187.861407

(C10)-(C12)-(C14)

 120.000000

 216.488007

(C10)-(C21)-(N22)

 120.000000

 255.193425

(C18)-(N15)-(N19)

 120.000000

 273.709525

(N15)-(C18)-(N16)  

   120.000000

 402.764879

(N15)-(N19)-(C17)

 120.000000

 315.342899

(C17)-(N16)-(C18)

 120.000000

 227.506158

(N16)-(C17)-(N19)

 120.000000

 402.764879

 

Table 4: Mulliken atomic charges and ZDO atomic charges of  letrozole

S.No

Atoms

ZDO atomic charges

Mulliken atomic charges

    1

   C

   -1.9406

 -2.0809

    2

    C

   -3.9991

 -4.0129

    3

    C

    3.9209

 4.1075

    4

    C

   -3.9999

 -4.0013

    5

    C

    1.9990

 2.0458

    6

    C

   -3.9920

 -4.0715

    7

    C

   -4.0000

 -4.0000

    8

    C

    3.9998

 4.0028

    9

    C

    3.9785

 4.0861

   10

    C

   -3.9997

 -4.0045

   11

    C

   -3.9969

 -4.0295  

   12

    C

   -3.7084

 -4.1784

   13

    C

    0.0285

 -0.0326

   14

    C

    3.7099

 4.1692

   15

    N

    5.0000

 5.0000

   16

    N

    5.0000

 5.0000

   17

    C

    4.0000

 4.0000

   18

    C

    4.0000

 4.0003

   19

    N

    5.0000

 5.0000

   20

    N

   -3.0000

 -3.0000

   21

    C

   -4.0000

 -4.0001

   22

    N

   -3.0000

 -3.0000

 

 

Table 5: Final energy evaluation.

S.No.

Force field  energy components

Values (au)

1

Molecular mechanics bond (Estr)

0.00831473

2

Molecular mechanics angle (Ebend)+ (Estr‑bend)

0.06093887

3

Molecular mechanics dihedral (Etor)

-0.00000000

4

Molecular mechanics ImpTor (Eoop)

0.00000000

5

Molecular mechanics vdW (EVdW)

0.07965959

6

Molecular mechanics coulomb (Eqq)

0.04748570

             Total

 0.11673929 a.u. (73.25507545 kcal/mol)  

 

CONCLUSION:

Arguslab software was used to study an aromatase inhibitor, 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile (letrozole). The excited state properties such as highest occupied molecular orbital’s (HOMO), lowest unoccupied molecular orbital’s(LUMO), amd electrostatic potential mapped density were created. The molecular mechanics potential energy(steric energy), heat of formation and self-consistent field (SCF) energy were calculated.

 

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Received on 02.09.2015                             Modified on 14.10.2015

Accepted on 20.10.2015      ©A&V Publications All right reserved

Res. J. Pharmacology & P’dynamics. 7(4): Oct.-Dec., 2015; Page 176-180 DOI: 10.5958/2321-5836.2015.00035.X