IndoChem


Molecular docking, Endophyte, Chaetomium, Breast Cancer

JURNAL FARMASI SAINS DAN KOMUNITAS, Mei 2016, hlm. 35-43   Vol. 13 No. 1 
ISSN: 1693-5683 

*Corresponding author: Maywan Hariono 

Email: ionehar@gmail.com   

 

MOLECULAR DOCKING OF COMPOUNDS FROM Chaetomium Sp. AGAINST HUMAN 

ESTROGEN RECEPTOR ALPHA IN SEARCHING ANTI BREAST CANCER 

 
Maywan Hariono1*), Rollando2 

1Faculty of Pharmacy, Sanata Dharma University, Maguwoharjo, Sleman, Yogyakarta 55282, Indonesia 

 2Program of Pharmacy, Faculty of Science and Technology, Ma Chung University, Malang 65151, 

Indonesia 

 

Received May 4, 2016; Accepted May 27, 2016 

 

Abstract: A study on molecular docking-based virtual screening has been conducted to select virtual hit of 

compounds, reported its existence in fungal endophytes of Chaetomium sp. as cytotoxic agent of breast 

cancer. The ligands were docked into Human Estrogen Receptor alpha (HER) as the protein which 

regulates the breast cancer growth via estradiol-estrogen receptor binding intervention. The results 

showed that two compounds bearing xanthone and two compounds bearing benzonaphtyridinedione 

scaffolds were selected as virtual hit ligands for HER leading to the conclusion that these compounds 

were good to be developed as anti breast cancer. 

 

Keywords:  
 

 

INTRODUCTION 

In family Chaetomiaceae (Ascomyta), 

Chaetomium sp. is a genus employing species 

broadly distributed among hundred marine and 

terrestrial natural products (Ferlay et al, 2007; 

Zhang et al, 2012). To date, about 200 compounds 

were reported as the chemical constituents from this 

genus (Li et al, 2011). This genus employs either 

bacterial or fungal endophyte which is currently 

being a trending topic in searching new source of 

biological active compounds due to its capability to 

be cultivated in abundance yields (Yang et al, 

2011). This is helpful to overcome the problem in 

isolating a single compound from raw materials 

which is normally using multistep extractions as 

well as fractionations (Hussain et al, 2012).  

As characterized in general natural product 

compounds, these endophyte from Chaetomium sp. 

also posses diverse biological activities such as 

antibacterial, antioxidant, anti-inflammatotry, 

antileishmanial and many others (Ruch, Cheng, and 

Klaunig, 1989). The fungal endophyte is living 

symbiotically in between the plant cells (Strobel, 

2003). Some plants have been identified its 

presence of Chaetomium sp. are Vinca rosea, Taxus 

braxifollia (Zhao et al, 2010), Phyllantus amarus 

(Kandavel and Sekar, 2015), Ginko biloba (Li et 

al, 2011), and so forth. Uniquely, the chemicals 

contained in the endophyte often highly related 

with the identity compounds in the plant of 

origins. For example is vincristine, the 

chemotherapeutics for cancer which is contained 

in Vinca rosea also found in its fungal endophyte 

(Kumar et al, 2013). Likewise, taxol was 

characterized in the fungal endophyte of Taxus 

braxifollia (Stierle, Strobel, and Stierle, 1993).  

Two mentioned plants were used clinically 

as the anti-cancer, a disease which is too tough to 

be controlled due its complicated life cycle and 

molecular mechanism. Breast cancer is one of the 

high prevalence cancers with about 1.7 million 

incidents annually (Lane, 2006). Therefore, the 

discovery and development of new anti-cancer is 

continuously needed especially to those resistant 

cancer genes.  

Computational studies in a virtual 

identification were broadly used in the screening 

of natural product database as bioactive 

compounds. This reduces the time, budget and 

safety in wet lab experiment since the sample to be 

tested is selected based on the mathematical value 

of drug-receptor interaction associating with its in 



Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

36   Maywan Hariono and Rollando      
 

vivo pharmacodynamic behaviours (Kitchen et al, 

2004). In this present study, we virtually screen 27 

compounds being identified in fungal endophyte of 

Chaetomium sp. to be selected as the hit compounds 

by docking them into one of the protein targets in 

the breast cancer cell, i.e., human estrogen receptor 

alpha (HER) DNA binding protein domain. 

  

EXPERIMENTAL 

The computer used in this study was a PC 

with Core 2 Duo processor 2.93 GHz and 2 GB of 

RAM. The operating system of the PC is 

Windows8. Docking the compounds  into human 

estrogen receptor alpha (HER; PDB 1G50) was 

carried out  to predict affinity of  chemical 

substances which are reported presenting in 

Chaetomium sp. from diverse plants. The ligands 

were sketched and geometrically minimized using 

ACD Chemsketch (www.acdlabs.com) and Marvin 

Sketch (www.chemaxon.com), respectively. The 

ligands and proteins were then prepared using 

AutoDockTools 1.5.6 (www.autodock.scripps.edu). 

The proteins were added with polar hydrogen and 

given by kollman charge whereas the ligands were 

given by gasteiger charges. The grid was centered 

on each protein binding site and the docking was 

then performed using AutoDock Vina embedded in 

PyRx version 8.0 (www.autodock.scripps.edu). The 

docking results were obeserved as free energy of 

binding (Gbind) and the selected docking pose was 

visualised using Discovery Studio 3.5 

(www.accelyrs.com). 

 

RESULTS AND DISCUSSION 

There have been well characterized that 

estrogen controls the breast cancer by stimulating 

the expression of certain genes (Horwitz and 

McGuire, 1978). Estrogen receptor with its helix 

H12 provides the binding site for estradiol as the 

messenger to dimerize and expose the SF-2 region. 

This will attract the Co-activator to bind leading to 

nucleic acid transcription during the breast cancer 

cell replication. The side chain containing ASP351 

is crucial to antagonism.  

The antagonist must contain an amine group 

of the correct basicity such that it ionizes and 

forms the interaction with ASP351, and it must be 

of the correct length and flexibility to place the 

amine in the correct position for binding (Patrick, 

2013). Several crystal structures of human 

estrogen receptor α ligand-binding domain (hERα 

LBD) complexed with agonist or antagonist 

molecules have previously been solved. The 

binding site was characterized where in estradiol 

bound to, by interacting with GLU353, ARG394, 

PHE404 and HIS524 via electrostatics, pi-pi and 

hydrogen bon interaction, respectively (Eiler et al, 

2001) The binding of estradiol as the chemical 

messenger is presented in Figure 1. 

 

 
Figure 1. The chemical interaction between estradiol and HER (a) 3D structure and (b) 2D structure. 

The protein was presented as ribbon and visualized using Discovery Studio 3.5 (www.accelrys.com) 
 

 

 

 

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Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

Molecular Docking of Compounds from…….   37 
 

Table 1. Compounds of Chaetomium sp. from diverse plants 

CH3

CH3

OH
CH3

CH3

H

H
CH3

CH3

H

 
HWergos 

CH3
CH3

OH
CH3

CH3

H

CH3

CH3

H
CH3

OO

 
 

HWergos58 

N
H

NH

O

O

O

OH  
 Latef1 

O

OH

O  
Latef2 

O

OH

O

OH

 
Latef3 

N

N

O

O

O OH

 
Latef4 

N

NH

O

OH

O OH

 
Latef5 

N

N

OH

OH

O

OH 
  Latef6 

O

OH

CH3

CH2

O

OH

CH3

CH3

 
Marwah1 

 

 

O

O

CH3

CH2
O

O CH3

CH3

O

CH3

CH3

O

 
Marwah2 



Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

38   Maywan Hariono and Rollando      
 

O
O

CH3

CH2

O

O
CH3

Cl
O

Cl
O

O
CH3

F
F

F

FF

F
O

CH3
 

Marwah3 

O

O
CH3

CH2

O
O

CH3

Cl
O

Cl
O

F

F

F

O
CH3

F

FF
O CH3

 
Marwah4 

 

O

O

CH3

CH2
O

O

CH3

Cl

O

ClO

F

F
F

O
CH3

FF

F

O
CH3

 
Marwah5 

 

O
OH CH3 

Marwah6 

O

O

CH3

CH2

Cl
O

OCH3 F

F

F

 
Marwah7 

 

OH

O CH3

O
CH3  

PengLi 

 

 

 

O

Cl

O

CH3

H

CH3

O

O
O

CH3

H

CH3

H

OH

CH3  
Qin1 

O

Cl

O

CH3

OH

CH3

O

O
O

CH3

H

CH3

H

OH

CH3  
Qin2 



Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

Molecular Docking of Compounds from…….   39 
 

N
H

NH

O

H
O

CH3
CH3

O

O

CH3

O

CH3

 
Qin4 

O

O OH

O

H

H
CH3

O
CH3

O
CH3

 
Wang1 

O

O
OH

OH
O

CH3Cl

O
CH3  

Wang2 

O

O

OHCH3

OH

OH

 
Wang3 

 

 

O

O

OHCH3

OH

O

CH3
 

Wang4 

O

CH3

O

CH3

O
CH3

 
Wang5 

NH

NH

OH

CH3

CH3

OH

O

O

O

O

O
CH3

CH3

O

O
O

CH3 CH3

 
WP1 

NH

NH

OH

CH3

CH3

OH

O

O

O

O

O
CH3

CH3

O

O
O

CH3 CH3

 
WP2 

  

In searching new active ligands, a number of 27 

compounds (see Table 1) from Chaetomium sp., 

was utilized as the database to be virtually screened 

using 1G50 as the protein target (Marwah et al, 

2007; Abdel-Lateff, 2008; Qin et al, 2009; Li et al, 

2011; Wang et al, 2012; Wang et al, 2015; Li et al, 

2015;). As results, Table 2 presented the Gbind, the 

amino acids which contribute to its binding via H-

bonding along with its H-bond distances. The order 

of compounds was ranked from the lowest Gbind 

to the highest one.  

The Gbind was observed at range -9.2 to -4.9 

kcal/mol for virtual active compounds while 

inactive compounds were indicated at range -4.2 to 

9.4 kcal/mol. There are six compounds found to be 

low in Gbind but they are not bound to the active 

site as no hydrogen bond being observed in their 

poses. This might be due to the van der Waals 

contribution which is normally not as essential as 



Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

40   Maywan Hariono and Rollando      
 

hydrogen bond. Van der Waals role in the ligand-

protein binding is normally to support or stabilize 

the pose via dipole induced dipole such as pi-pi, pi-

cation and or pi-sigma interactions. Van der waals 

interaction has a weak affinity, therefore, this is 

normally less priority in the ligand-protein 

interaction. Although virtual screening has been 

developed as a fast and accurate scoring function, 

however, no single scoring can satisfy the 

peculiarities of each target system (Li et al, 2009). 

In further virtual hit selection, the priority 

goes to the ligands which have lower Gbinds and 

similar binding modes with the reference (Yang et 

al, 2013). A diverse hydrogen bond interaction was 

demonstrated by all ligands fit into the active site 

with the corresponding amino acid residues such 

as GLU323, PRO324, PRO325, LEU345, 

LEU346, GLU353, TRP393, ARG394 and 

LYS449. However, among those mentioned amino 

acid residues, interactions with GLU353 and 

ARG394 were the most prevalent and it was 

suggested to be important as these interaction were 

also possessed by the reference ligand. Therefore, 

compounds having interaction with these types of 

residue were proposed to be the virtual hits ready 

for further optimization. Figure 2 illustrated the 

superimposition of 27 ligands in the active site of 

1G50, whereas Figure 3 illustrated the ligands-

protein interaction of some representative virtual 

hit compounds.  
 

Table 2. The Gbinding of 27 ligands were docked into hERα LBD (PDB 1G50). 
Ligands Gbind (kcal/mol) Amino acid residues H-bond distance (Å) 

Wang3 -9.2 ARG394 1.98 

Wang4 -8.8 GLU353, ARG394 1.84, 1.90 

Latef1 -7.8 NHB NA 

Latef6 -7.8 NHB NA 

Latef4 -7.7 PRO324, ARG394, LYS449 2.44, 2.19, 1.90 

Latef5 -7.6 GLU323, ARG394, LYS449 2.27, 2.14, 2.41 

Wang5 -7.2 NHB NA 

HWergos58 -6.8 TRP393 2.12 

Marwah6 -6.8 NHB NA 

Marwah5 -6.6 ARG394, LYS449 2.07, 2.29 

HWergos -6.5 NHB NA 

Marwah4 -6.5 TRP393, ARG394, LYS449 2.10, 1.69-1.87, 2.49 

Wang1 -6.5 NHB NA 

WP2 -6.5 LEU345, LEU346, ARG394 1.95, 2.49, 1.59 

Marwah2 -6.3 TRP393, LYS449 2.20, 1.80 

Wang2 -6.1 LYS449 2.20 

PengLi -5.9 PRO325, ARG394 2.10, 1.86 

Marwah1 -5.8 TRP393 2.20 

Marwah7 -5.7 TRP393, LYS449 1.93, 2.39 

Latef3 -5.5 ARG394, LYS449, 2.02, 2.22 

Qin1 -5 TRP393 1.78 

Latef2 -4.9 ARG394, LYS449 2.42, 2.05 

Qin2 -4.2 NHB NA 

Marwah3 0.7 NHB NA 

Qin3 3.3 NHB NA 

WP1 6.1 NHB NA 

Qin4 9.4 PRO325 1.98 
NHB = No Hydrogen bond; NA = Not Applicable 

 



Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

Molecular Docking of Compounds from…….   41 
 

 
Figure 2. The superimposition of 27 ligands from Chaetomium sp. docked to the active 

site of HER (PDB 1G50). The protein was presented as surface and visualized using 

Discovery Studio 3.5 (www.accelrys.com).  

 
 

 
Figure 3. The ligand-binding interaction of four virtual hit compounds from Chaetomium sp. docked to the 

active site of HER (PDB 1G50): (a) Wang3 (b) Wang4, (c) Latef4 and (d) Latef5. The protein was presented as 

ribbon and visualized using Discovery Studio 3.5 (www.accelrys.com).  

 

Compounds bearing xanthone (Wang3 and 

Wang4) and benzonaphtyridinedione (Latef4 and 

Latef5) could be good scaffolds for further lead 

optimization of cytotoxic agent against breast 

cancer by targeting HER DNA binding protein 

domain. Xanthone has been widely published as 

anticancer due to triple heteroaromatic ring which 

acts a DNA intercalating agent. The planar system 

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Jurnal Farmasi Sains dan Komunitas, 2016, 13(1), 35-43 
 

42   Maywan Hariono and Rollando      
 

of heteroaromatic ring takes over the space in 

between two layers of nucleic acid pairs and 

therefore disrupts the shape of the helix. This action 

occurred at either minor or major groove which 

prevents the DNA replication as well as its 

transcription. On the other hand, 

benzonaphtyridinedione has been reported as 

tyrosine kinase inhibitors which play roles in signal 

transduction which regulates the intercellular 

communication, thus it is a good approach for the 

therapeutic intervention against pathological 

processes such as proliferation, inflammation and 

cancer.  

 

CONCLUSIONS 

Fungal endophyte has been recognized as the 

new source of bioactive compounds from natural 

products. One of genus widely cultivate this fungi is 

Chaetomium sp. spread over plant has been well 

known in producing high value of compounds for 

many pharmacological activities. The advantage of 

this material is its capability to be cultivated in a 

high yield via biotechnology process compares to 

the traditional fabrication that needs more 

plantation. In order to increase the knowledge in 

developing new anticancer drug from natural 

product, a molecular docking based virtual 

screening has been approached to select some hit 

compounds to be active as breast cancer cytotoxic 

agent by HER DNA binding protein domain 

intervention. Compounds bearing xanthone and 

benzonaphtyridinedione were selected as the most 

active ligand against the protein target. In 

conclusion, Chaetomium sp. is strongly suggested to 

be developed as the source for bioactive compounds 

concerning on anticancer agent. However, further 

retrospective validation is required to have a 

validated protocol in virtual screening leading to the 

features of ligand to be suitable as HER 

antagonist. 

   

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