In Silico Analysis of Boron Derivate Compounds as Potential ER-α

Inhibitor

Urip Harahap

*, Ginda Haro

, Hari Purnomo

and Denny Satria

Department of Pharmacology, Universitas Sumatera Utara, Medan, Indonesia.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia

Department of Pharmacology, Universitas Sumatera Utara, Medan, Indonesia.

Keywords: BornUSU I, BornUSU II, ER-α, Inhibitor, In silico.

Abstract: Background :BornUSU I or Boronhafagama I (1,5-bis(4-hydroxyphenyl)-3-oxa-1,5-diaza-2,4-diboropentane-

2,4-diol) and BornUSU II or Boronhafagama II (1-(4-hydroxynaphthalen-1-yl)-5-(4-hydroxyphenyl)-3-oxa-

1,5-diaza-2,4diboropentane-2,4 diol) are boron derivate compounds which are boron neutron captured therapy

(BNCT) candidates. Estrogen receptor alpha (ER-α) appear a crucial assignment in the growth and

development of bone, breast and uterine pathology especially in human cancers, including breast

cancer.Tamoxifen has been used as a cure for women who have been identified breast cancer for around four

decades. Tamoxifen has high risks, such as the risk endometrial malignancy and hyperplasia varies from 1.5

to 6.9 fold after cumulative and long duration usage. Methods: In silico docking using PLANTS programme

and visualized by Pymol programme. The model of three dimension enzyme structures used in this research

was ER-α, binding pocket with the Protein Data Bank (PDB) code 3ERT. Results: Two and three dimension

of compounds and 4-hydroxytamoxifen as the standard were generated using Marvin Sketch program. Both

compoundsand standards inhibitedER-α with docking score -92.1697; -

1 INTRODUCTION

Breast cancer is the most incidence cancer and the

second famous cause of cancer death in females

(Jemal, et al., 2010). Then, breast cancer ranks as the

fifth cause of death from cancer on the whole and the

most frequent cause of cancer death in women in less

developed countries, and the second cause of cancer

death in developed countries after lung cancer. A

recent study published which breast cancer is leading

in the estimate new cancer cases, and the second most

general death cause among women suffering from

cancer in the America (Siegel, et al., 2010).

Estrogen plays a critical role in the growth and

development of bone, breast and uterine pathology.

There are two subtypes of estrogen receptor, ER-α

(Estrogen Receptor alpha) and ER-β (Estrogen

Receptor beta). ER-α plays a role in cell proliferation

and has been found in the endometrial, breast cancer

and ovarian stromalcell, as well as in the

hypothalamus (Levin, 2005). Tamoxifen is also

prescribe for breast cancer patients as hormonal

inhibitor. The tamoxifen-bound ER complex inhibits

the genes from being switched on by Estrogen,

leading to the prevention of the Estrogenic leverage

which accountable for cancer cell proliferation

(Chang, 2012). Tamoxifen has high risks in women

who have been it in their therapy (Subarnas, et al.,

2015) after cumulative and long duration wear

(Cohen, et al., 2003). With all of these risks many

patients regardless this therapy. Thus, alternative

treatments are needed.

Boron Neutron Capture Therapy (BNCT) is an

progress form of radiotherapy technique which is

potentially supreme to all conventional techniques for

cancer treatment, as it is targeted at killing individual

cancerous cells with minimal harm to surrounding

healthy cells (Payudan. Et al., 2016). Boronic

compounds has been before used in imaging and

medicinal chemistry offering unique advantages

associated with its low toxicity and stability (Trippier,

and McGuigan, 2010). BornUSU 1 (1,5-bis(4-

hydroxyphenyl)-3-oxa-1,5-diaza-2,4-diboropentane-

2,4-diol) or Boronhafagama I and BornUSU 2 or

Boronhafagama II (1-(4-hydroxynaphthalen-1-yl)-

5-(4-hydroxyphenyl)-3-oxa-1,5-diaza-

2,4diboropentane-2,4-diol). The chemical structures

814

Harahap, U., Haro, G., Purnomo, H. and Satria, D.

In Silico Analysis of Boron Derivate Compounds as Potential ER- Inhibitor.

DOI: 10.5220/0010091808140817

In Proceedings of the International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches (ICOSTEERR 2018) - Research in Industry 4.0, pages

814-817

ISBN: 978-989-758-449-7

of BornUSU I, BornUSU II, tamoxifen and 4-

hydroxy tamoxifen are showed in Figure 1.

Computational analysis are being expanded to

evaluation in predict the compounds activity. In silico

approaches contribute significantly to beginning

pharmaceutical research and notable in object

discovery. (Bharath, et al., 2011). The purpose of our

study was to identify how ER-α inhibitors are

working for cancer using in silico molecular docking

method. The purposes of this research was to assess

the activity of BornUSU I, BornUSU II, tamoxifen

and 4-hydroxy tamoxifen in inhibiton ER-α with in

silico method.

a b c

Figure 1. Structure of (a) BornUSU I, (b) BornUSU II, and (c) 4-hydroxy tamoxifen.

2 METHODS

Aspire E1-470 series operated by Windows 7 Home

Premium, Intel

Core

i3 -3217U (1,8 GHz, 3MB

L3 cache), 32-bit, hard disc drive 500 GB and RAM

memory 2 GB DDR3 L were used to run the

molecular docking process.

In silico docking using PLANTS program and

visualized by pymol programmee. Co Pen Drive

Linux KDE program was used to connecting

Windows operation system to Linux operation

system. The model of three dimension of enzyme

structure used in this research was ER-α binding

pocket with the Protein Data Bank (PDB) code 3ERT.

It was obtained through from

http://www.rscb.org/pdb. Two and three dimension

conformation models of BornUSU 1, BornUSU 2 and

4-hydroxy tamoxifen as the standard inhibitor were

generated by Marvin Sketch program.

3 RESULT

The Root Mean Square Deviation (RMSD) values

resulted from these ligand docking was 1.6276Å for

3ERT. The RMSD was obtained less than 2.0000 Å

indicating that the docking methods were valid

(Terstappen., and Reggiani, 2001). In silico docking

between BornUSU 1, BornUSU 2, tamoxifen and 4-

hydroxy tamoxifen into 3ERT binding pocket result

inthe docking scorein Table 1 isshowed the results of

docking score into 3ERTbinding pocket. Figure 2 and

3 are showed the results of visualization of BornUSU

1, BornUSU 2 and 4-hydroxy tamoxifen to ER-α

using pymol.

Table 1. Docking score between ligand and protein target

No Ligand Name

Dockin

Score

ER-α

1 4-hydroxy

tamoxifen

-99.0879

2 BornUSU I -92.1697

3 BornUSU II -100.1940

In Silico Analysis of Boron Derivate Compounds as Potential ER- Inhibitor

815

Figure 2. Visualization of interaction between.

(a) BornUSU 1 with ER-α

(b) BornUSU 2 with ER-α

Figure 3. Overlay interaction of 4-hydroxy tamoxifen,

BornUSU 1 and 2 with Receptor of Estrogen Alpha with

pymol.



a



Figure 4. Interaction of BornUSU I and BornUSU 2with

Receptor of Estrogen Alpha with pymol.

Visualization interaction of 4-hydroxy tamoxifen

with Estrogen alpha receptor (ER-α) shown at Picture

4. Some of amino acids from ER-α which is role in

the mechanism of action of 4-hydroxy tamoxifen are:

Met-242, Leu-346,Thr-347, Leu-349, Ala-350, Asp-

351, Glu-353, Trp-383, Leu-284, Leu-387, Met-388,

Leu-391, Arg-394, Phe-404, Glu-420, Met-421, and

Leu-428. Oxygen from hydroxyl group to form

hydrogen bond with water, Arginin-394(Arg-394)

and Glutamat-353(Glu-353), while Leusin- 387(Leu-

387) participate in stabilize hydrogen bond between

oxygen with both of amino acids which mentioned

above.

Several amino acids from ER-α which is role in

BornUSU I or in Boronhafagama I are Ile-386, Met-

357, Ala-382, Trp-383, Leu-384, Glu-385, Leu-387,

Met-388, Ile-389, Gly-390, Phe-445, Val-446, Lys-

449, Ile-452 and Ile-514.Several amino acids from

ER-α which is role in BornUSU II or Boronhafagama

II are Met-357, Trp-360, Ala-361, Leu-378, Leu-379,

Glu-380, Cys-381, Ala-382, Trp-383, Leu-384, Glu-

385, Ile-386, Leu-387, Gly-390, Phe-435, Leu-440,

Phe-445, Val-446, Leu-448, Lys-449, Ile-452, Leu-

453, Ser-456 and Ile-514.Although docking score of

BornUSU 2 is higher than 4-hydroxy tamoxifen but

this score is not significance. BornUSU 2 interaction

with 24 amino acids from ER-α while 4-hydroxy

tamoxifen interaction with 17 amino acids from ER-

α.

4 DISCUSSION

The docking score represents the binding affininty of

the ligand to the target protein. The docking of ER-α

target with compounds using docking procedure was

mentioned that all the computationally predicted

lowest energy complexes of ER-α is stabilized by

ICOSTEERR 2018 - International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches

816

intermolecular hydrogen bonds and stacking

interactions (Levin, 2005).

Docking score of BornUSU II were lower than

tamoxifen and 4-hydroxy tamoxifen but BornUSU I

is lower than 4-hydroxy tamoxifen and higher than

tamoxifen. In silico drug design can play a significant

role in all of stages of drug development from

preclicial assesment to the end of clinical

development (Levin, 2005). The results were

obtained at in silico screening have shown that it

represents the best step (way) to get an accurate result

in a short time and saving manner (Terstappen and

Reggiabi, 2001).

5 CONCLUSIONS

BornUSU I and II are boron derivate compounds.

They were showed to have the activity in inhibition

of cancer growth through ER-α pathways and they are

potential to develop as anticancer.

ACKNOWLEDGEMENT

We gratefully thank to Research CenterUniversity of

Sumatera Utara through Hibah Talenta “Hibah

Penelitian Guru Besar” for financial support in the

study.

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