In Silico Molecular Interaction Studies of Suberoylanilide Hydroxamic Acid and Its Modified Compounds with Histones Deacetylase Class II <i>Homo sapiens</i> as Curative Measure towards Cervical Cancer

doi:10.4236/eng.2013.510B043

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Engineering, 2013, 5, 203-206

http://dx.doi.org/10.4236/eng.2013.510B043 Published Online October 2013 (http://www.scirp.org/journal/eng)

In Silico Molecular Interaction Studies of Suberoylanilide

Hydroxamic Acid and Its Modified Compounds with

Histones Deacetylase Class II Homo sapiens as C urative

Measure towards C ervical Canc er

Usman Sumo Friend Tambunan1*, Arli Aditya Parikesit1, Tirtana Prasetia1, Djati Kerami2

1Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok, Indonesia

2Department of Mathematics, Faculty of Mathematics and Science, University of Indonesia, Depok, Indonesia

Email: *[email protected]

Received May 2013

ABSTRACT

The threat of cervical cancer is a serious problem for the women’s health. It is already known that the cause of cervical

cancer is definitely HP V (Human Papilloma Virus). The drug development is the most reasonable approach for coping

with HPV infection. The development of HDACi (Histon e Deacetylase inhib itor) is seen as a feasible method for curing

the threat of cervical cancer. Rational drug design is our utilized pipeline for drug development. The LigX MOE-based

method has been developed to investigate the molecular interaction of HDAC class II Homo sapiens with the designed

lead compound. The method has found that ligands 1c, 2a, and 2c are indeed feasible to be formulated as drug candi-

dates.

Keywords: Cervical Cancer; HPV; HDAC; S AHA; LigX; Dynamics Simulations

1. Introduction

The second most tangible cancer threat for woman is

cervical cancer that is caused by Human Papillomavirus

(HPV) [1,2]. There are several studies to date that strug-

gling to cope with HPV infection. The possible ap-

proaches are developing drugs and vaccine. To date,

there are numerous successful projects in HPV vaccine

and immunotheraphy development, and some of them

already reach the market [3-6]. Moreover, computational

approach of designing HPV vaccine is on sight as well

[7]. However, the vaccine could only feature as the pre-

vention agent, not curative one. In this end, drug devel-

opment is seen as one of the most promising methods of

curing HPV infection.

There are some anti-HPV drug development methods

in the market, but one of the feasible strategies for cer-

vical cancer therapy is the development of Histone dea-

cetylase inhibitor (HDACi) as the drug candidate [8,9].

The side effects of SAHA are well known in the medical

community by inhibiting immature osteoblasts [10]. Hence-

forth, the derivatives of SAHA have been developed for

mitigating those side effects. Moreover, the possible

modification on the SAHA functiona l groups is basically

numerous.

The objective of this research is to investigate the mo-

lecular interaction of our designed ligands, as SAHA

modified compounds, with the HDAC class II Homo

sapiens. In this end, it is expected that this study will

pave a way for developing drug candidates.

2. Methods

The whole method was utilized based upon the procedure

in [11,12]. The 3D structure of Homo sapiens class II

HDAC was prepared. The integrity of the protein and

ligand structure was optimized with Linux script and

Autodock tools [13]. The molecular docking and dynam-

ics procedure were conducted in accordance to the estab-

lished method [11,12]. The stages of molecular dynamics

are initialization, equilibration, and production. In order

to study the molecular interaction, th e LigX tool of MOE

2008.10 wa s utiliz e d.

3. Results and Discussion

The designated pipeline has eventually produced the de-

sired result. The autodock visualization of the active site

of HDAC class II Homo sapiens was shown in Figu re 1.

It is shown that the active site was hidden in the inner

crevice. In this end, a sophisticated pipeline was needed

to observe the ligand interaction within the crevice itself.

Corresponding author.

U. S. F. TAMBUNAN ET AL.

204

Figure 1. Visualization of the active site of HDAC class II

Homo sapiens.

We have prepared the best ligand based upon the pre-

vious study that has the best affinity and the lowest tox-

icity in accordance to the Lipinski’s Rule of Fiv e [12,14].

Each HDAC will be paired with SAHA as its standard

and one best ligand in order to observe their molecular

interaction. The interaction pair between ligand and

HDAC could be observed in Table 1.

The existing drug development pipeline has designed

three SAHA-derived ligands, namely 1c, 2a, and 2c [11],

[12]. LigX, as an integrated tool of MOE packages, has

been utilized by scientific community to evaluate the

structure-based ligand optimization. The Figure 1 shows

that the Zn2+ ion interaction with existing residues is

stronger in our ligand than SAHA. Thus, it is a direct

evidence that metal-based cofactor plays a role in the

protein-ligand interaction [15]. The electron distribution

of our ligands is more favorable than the standard, as

shown in all instances of Figure 2, because the electron

cloud is distributed more equally in all atoms of our li-

gands. Observation of contact residues and hydrogen

bonding of those ligands have shown that they are indeed

suitable to be developed as HDACi, as the molecular

interaction is stronger than SAHA.

4. Conclusion

The computational effort of this study has shown that the

electronic interaction of the ligand with the receptor is

the main factor for the well being of a chemical reaction.

The molecular interaction study has shown that our li-

gands are indeed feasible to be developed as drug candi-

SAHA (standard) Our Ligands [11,12]

HDAC 4

(a) (b)

HDAC 5

U. S. F. TAMBUNAN ET AL.

205

HDAC 6

(e)

(f)

HDAC 7

(g) (h)

HDAC 9

(i) (j)

Figure 2. The molecular interaction visualization of LigX tools after molecular dynamics production session at 5000 ps for: (a)

HDAC4-SAHA; (b) HDAC4-2c; (c) HDAC5-SAHA; (d) HDAC5-2a; (e) HDAC6-SAHA; (f) HDAC6-2c; (g) HDAC7-SAHA;

(h) HDAC7-2c; (i) HDAC9-SAHA; (j) HDAC9-1c.

Table 1. The HDAC class II Homo sapiens pairing with the

ligand.

Enzim Ligan

HDAC 4 SAHA 2c

HDAC 5 SAHA 2a

HDAC 6 SAHA 2c

HDAC 7 SAHA 2c

HDAC 9 SAHA 1c

dates due to their strong affinities with the receptors.

5. Acknowledgements

The funding for the research and the conference is sup-

ported by Skema Bantuan Seminar Luar Negeri/Program

Insentif Peneliti Universitas Indonesia Tahun 2013

(BOPTN) Submission #1511 and Hibah BOPTN Ditjen

Dikti No: 2788/H2.R12/HKP.05.00/2013. Usman Sumo

Friend Tambunan and Djati Kerami supervised this re-

search; Tirtana Prasetia was working on the technical

details, while Arli Aditya Parikesit prepared the English

manuscript and re-verified the computation data.

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