Computer-Aided Molecular Design of a Histone Deacetylase (HDAC) Inhibitor,

N-Hydroxy-N-Phenyloctanediamide (Vorinostat)

 

I.E. Otuokere and F. J. Amaku

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

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

 

Abstract:

Vorinostat ,(N-hydroxy-N-phenyloctanediamide) is in a class of medications called histone deacetylase (HDAC) inhibitors. It is a good chemotherapeutic agent for treating cutaneous T-cell lymphoma (CTCL, a type of cancer) in patients whose disease has not improved, has gotten worse, or has come back after taking other medications.  Conformational analysis and geometry optimization of vorinostat was performed according to the Hartree-Fock (HF) calculation method by ArgusLab 4.0.1 software.  Molecular mechanics calculations were based on specific interactions within the molecule. These interactions included stretching or compressing of bond beyond their equilibrium lengths and angles, torsional effects of twisting about single bonds, the Vander Waals attractions or repulsions of atoms that came close together, and the electrostatic interactions between partial charges in vorinostat due to polar bonds.  The steric energy for vorinostat was calculated to be 0.030859 a.u. (19.364457 kcal/mol).  It was concluded that the lowest energy and most stable conformation of vorinostat was 19.36445736 kcal/mol).  The most energetically favourable conformation of  vorinostat was found to have a heat of formation of 115441.244100 kcal/mol. The self-consistent field (SCF) energy was calculated by geometry convergence function using RHF/AM1 method  in ArgusLab software. The most feasible position for  vorinostat  to act as histone deacetylase (HDAC) inhibitor was found to be -116.682947 au (-73219.720900 kcal/mol).

 

KEY WORDS: Arguslab, vorinostat, molecular mechanics, inhibitor, cancer

 

Introduction:

Vorinostat, (N-hydroxy-N-phenyloctanediamide) is a good chemotherapeutic agent for treating cutaneous T-cell lymphoma (CTCL, a type of cancer) in patients whose disease has not improved, has gotten worse, or has come back after taking other medications. Vorinostat is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by killing or stopping the growth of cancer cells [1].

 

The mechanism for the antiproliferative effect of vorinostat activity is believed to be ancord on it ability to inhibit histone deacetylase (HDAC) and this result to the accumulation of acetylated proteins, including histones. The inhibitory action of vorinostat is known to have multiple cellular effects [2– 4]. These effects include an alteration in the transcription of a finite number of genes via acetylation of histones and transcription factors, as well as nontranscriptional effects such as cell cycle arrest via inhibition of mitosis [5,6]. Vorinostat has been shown to impact the expression of several genes, some of which are induced while others are         repressed [7].  Further research into the mechanism(s) of action of vorinostat as well as delineation of its clinical utility in various cancer types should help formulate rational combinations with other chemotherapeutic agents that may provide synergistic or additive antitumour efficacy [8,9]. Based on a mechanistic rationale, vorinostat has the potential to be combined with several different types of anticancer therapies, including radiation.

 

Molecular surface charges of drugs determines the level of interaction of the drugs with the receptor, these charges are partial atomic charges obtained from calculations carried out by the methods of computational chemistry which can be used to characterize the electronic charge distribution in a molecule and the bonding, antibonding, or nonbonding nature of the molecular orbitals for particular pairs of atoms. To develop the idea of these populations, a real, normalized molecular orbital composed from two normalized atomic orbitals is taken into consideration by calculating the density matrix terms.

 

The Mulliken charges, are obtained , from the difference between the number of electrons on the isolated free atom, and the gross atom population as shown in equation

1. .   , ZDO charges can also be generated from Arguslab using the AM1 parameterized method. In the zero deferential overlap (ZDO) approximation, the product of two deferent atomic orbitals is set to zero. The integral which survives the ZDO approximation was partly computed using the uniform charge sphere and the rest parameterized. 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 deference in energy from one conformation to the next.

 

 

MATERIALS AND METHOD:

All conformational analysis (geometry optimization) study was performed on a window based computer using Argus Lab 4.0.1 [10] and ACD Lab Chem Sketch [11] software. Vorinostat structure was sketched with ACD Lab Chem Sketch software and saved as MDL molfiles (*mol). The vorinostat structure was generated by Argus lab, and minimization was performed with UFF molecular mechanics method [12, 13]. The minimum potential energy was calculated by using geometry convergence function in Arguslab software. Surfaces created to visualize excited state properties such as highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and electrostatic potentials (ESP) mapped density. The minimum potential energy was calculated for vorinostat through the geometry convergence map. Mulliken atomic charges and ZDO atomic charges of N-hydroxy-N-phenyloctanediamide (Vorinostat) were determined using AM1/RHF method when the net charge was -1 and valence electrons 88.

 

RESULTS AND DISCUSSION:

Prospective view and calculated properties of vorinostat molecule are shown in Figure 1. Figure 2 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 electrostatic potential is a physical property of a molecule and relates to how a molecule is first “seen” or “felt” by another approaching species.

 

 

A distribution of electric charge creates an electric potential in the surrounding space. A positive electric potential means that a positive charge will be repelled in that region of space. A negative electric potential means that a positive charge will be attracted. A portion of a molecule that has a negative electrostatic potential will be susceptible to electrophilic attack – the more negative the better. Quick Plot ESP mapped density generates an electrostatic potential map on the total electron density contour of the molecule [10]. The electron density surface depicts locations around the molecule where the electron probability density is equal. This gives an idea of the size of the molecule and its susceptibility to electrophilic attack.  The active conformation and electron density mapped of vorinostat by ACDlabs-3D viewer software are shown in Figure 3 and 6 respectively.

 

Figure 4 and 5, shows the highest occupied molecular orbital’s and the lowest unoccupied molecular orbital’s of vorinostat molecule. Self-consistent field energy of verinostat is shown in Figure 7. Atomic  coordinates of molecule is given in Table1,  bond length and bond angles are given in Table 2 and 3 respectively, which are calculated after geometry optimization of molecule from Arguslab  using molecular mechanics calculation. Table 4 shows calculated steric energy of vorinostat  molecule. Table 5 shows the ZDO and mulliken atomic charges of vorinostat. The steric energy and heat of formation calculated for vorinostat are   0.030859 a.u. (19.364457 kcal/mol) and 115441.244100 kcal/mol respectively. SCF energy was found to be -116.682947 au (-73219.720900 kcal/mol) as calculated by RHF/AM1 method using  ArgusLab 4.0.1 suite.

 

Table 1: Atomic coordinates of  vorinostat

S.No

Atoms

X

Y

Z

       1

   C

   21.887000

 -36.863400

0.000000

      2

  C

   21.887000

 -38.193400

0.000000

      3

   C

   20.735100

 -36.198400

0.000000

      4

   C

   20.735100

 -38.858400

0.000000

      5

   C

   19.583300

 -36.863400

0.000000

      6

   C

   19.583300

 -38.193400

0.000000

      7

   N

   20.735100

 -34.868400

0.000000

      8

   C

   21.886900

 -34.203400

0.000000

      9

   C

   21.886900

 -32.873400

0.000000

     10

   O

   23.038700

 -34.868400

0.000000

     11

   C

   23.038700

 -32.208400

0.000000

     12

   C

   23.038700

 -30.878400

0.000000

     13

   C

   24.190500

 -30.213400

0.000000

     14

   C

  24.190500

 -28.883400

0.000000

     15

   C

   25.342300

 -28.218400

0.000000

     16

   C

   25.342300

 -26.888400

0.000000

     17

   N

   26.494100

 -26.223400

0.000000

     18

   O

   24.190500

 -26.223400

0.000000

     19

   O

   26.494100

 -24.893400

0.000000

     20

   H

   19.583300

 -34.203500

0.000000

     21

   H

   27.645900

 -26.888400

0.000000

     22

   H

   27.645900

 -24.228400

0.000000

 

Table 2: Bond length of vorinostat.

Atoms

Bond length

(C1)-(C2)

     1.458000 

(C1)-(C3)

     1.323387

(C2)-(C4)

     1.323387 

(C3)-(C5)

     1.458000 

(C3)-(N7)

     1.419751

(C4)-(C6)

     1.458000 

(C5)-(C6)

     1.323387 

(N7)-(C8)

     1.346235 

(N7)-(H20)

     1.048529 

(C8)-(C9)

     1.464000 

(C8)-(O10)

     1.260307 

(C9)-(C11)

     1.464000

(C11)-(C12)

     1.464000

(C12)-(C13)

     1.464000 

(C13)-(C14)

     1.464000 

(C14)-(C15)

     1.464000 

(C15)-(C16)

     1.464000 

(C16)-(N17)

     1.346235 

(C16)-(O18)

     1.260307 

(N17)-(H21)

     1.048529 

(N17)-(O19)

     1.323604 

 (O19)-(H22)               

      1.009568

 

 

Table 3: Bond angles of vorinostat.

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)-(N7)

 120.000000

 300.697530

(C2)-(C4)-(C6)

 120.000000

 216.488007

(C5)-(C3)-(N7)

 120.000000

 260.801534

(C3)-(C5)-(C6)

 120.000000

 216.488007

(C3)-(N7)-(C8)

 120.000000

 220.592895

(C3)-(N7)-(H20)

 120.000000

 112.353122

(C4)-(C6)-(C5)

120.000000

 216.488007

(C8)-(N7)-(H20)

 120.000000

 124.171616

(N7)-(C8)-(C9)

 120.000000

 279.479738

(N7)-(C8)-(O10)

 120.000000

 421.698151

(C9)-(C8)-(O10)

 120.000000

 275.966448

(C8)-(C9)-(C11)

120.000000

 186.134654

(C9)-(C11)-(C12)

 120.000000

 186.134654

(C11)-(C12)-(C13)

 120.000000

 186.134654

(C12)-(C13)-(C14)

 120.000000

 186.134654

(C13)-(C14)-(C15)

 120.000000

 186.134654

(C14)-(C15)-(C16)

 120.000000

 186.134654

(C15)-(C16)-(N17)

 120.000000

 279.479738

(C15)-(C16)-(O18)

 120.000000

 275.966448

(N17)-(C16)-(O18)

 120.000000

 421.698151

(C16)-(N17)-(H21)

 120.000000

 124.171616

(C16)-(N17)-(O19)

 120.000000

 295.314382

(H21)-(N17)-(O19)

 120.000000

 154.086979

(N17)-(O19)-(H22)

 120.000000

 178.031818

 

Table 4: Mulliken atomic charges and ZDO atomic charges of vorinostat.

S.No

Atoms

ZDO atomic charges

Mulliken atomic charges

1

C

4.0000

4.0000

2

C

4.0000

4.0000

3

C

3.9999

4.0001

4

C

4.0000

4.0000

5

C

4.0000

4.0000

6

C

4.0000

4.0000

7

N

4.9921

4.9927

8

C

3.0381

3.3563

9

C

-3.8383

-4.1195

10

O

2.8118

2.7730

11

C

-3.9999

-4.0023

12

C

-4.0000

-4.0000

13

C

-4.0000

-4.0000

14

C

-4.0000

-4.0000

15

C

-4.0000

-4.0000

16

C

-4.0000

-4.0000

17

N

-3.0000

-3.0000

18

O

-2.0000

-2.0000

19

O

-2.0000

-2.0000

20

H

0.9963

0.9996

21

H

-1.0000

-1.0000

22

H

-1.0000

-1.0000

 

CONCLUSION:

Computer-aided molecular design of vorinostat has been performed. Geometry optimization was performed to determine the steric energy, heat of formation and self-consistent field (SCF) energy of vorinostat using Arguslab software. The excited state properties such as highest occupied molecular orbital’s (HOMO), lowest unoccupied molecular orbital’s (LUMO), and electrostatic potential mapped density were created. The molecular mechanics method calculated the energy as a function of the coordinates and energy minimization is an integral part of method.

 

Table 5: Final energy evaluation.

S.No.

Force field  energy components

Values (au)

1

Molecular mechanics bond (Estr)

0.00269864

2

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

0.00372387

3

Molecular mechanics dihedral (Etor)

-0.00000000

4

Molecular mechanics ImpTor (Eoop)

0.00000000

5

Molecular mechanics vdW (EVdW)

0.02443669

6

Molecular mechanics coulomb (Eqq)

0.00000000

Total

 0.03085920 a.u. (19.36445736 kcal/mol)

 

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Received on 02.09.2015       Modified on 25.09.2015

Accepted on 06.10.2015      ©A&V Publications All right reserved

Research J. Science and Tech. 7(4):Oct. – Dec. 2015; Page 212-216

DOI: 10.5958/2349-2988.2015.00030.3: