molecular docking of lung cancer proteins against …

www.wjpr.net Vol 3, Issue 3, 2014.

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Bhagavathi et al. World Journal of Pharmaceutical Research

MOLECULAR DOCKING OF LUNG CANCER PROTEINS AGAINST

SPECIFIC DRUG TARGETS

*Bhagavathi S1, Dr.Gulshan Wadhwa2, Dr. Anil Prakash3

1Research Scholar, Department of Biotechnology & Bio Informatics Centre, Barkatullah

University, Bhopal-462026, India 2 Joint Director , Department of Biotechnology, Ministry of Science &Technology, Govt. of

India, New Delhi-110003 3Professor, Department of Microbiology & Bio Informatics Centre, Barkatullah University,

Bhopal-462026, India

ABSTRACT The key proteins that are responsible for Lung cancer are Polo Like

Kinase 1, Thrombomodulin, Trophinin and Matrix MetalloProteinase.

These target proteins were modeled to predict their three dimensional

structures and subjected to active site analysis tool to determine the

amino acids actively involved in the binding site function. Four drug

targets Vorinostat, Gemcitabine, Paclitaxel and Etoposide were docked

with the target proteins to detect the binding efficacy of the drug. The

score suggests Gemcitabine effective against Polo like kinase 1 and

Vorinostat acts as better inhibitor against Thrombomodulin and Matrix

MetalloProteinases receptor. Paclitaxel is found to inhibit Trophinin

forming a stable docked structure.

Keywords: Lung cancer, Vorinostat, Gemcitabine, Paclitaxel,

Etoposide, Polo Like Kinase 1, Thrombomodulin, Trophinin, Matrix

Metallo Proteinase.

INTRODUCTION

Cancer remains an important cause of chronic illness. Better understanding of various genes

and proteins and their implications at the cellular and molecular levels helps in identifying

appropriate preventive/diagnostic measures. Lung cancer, the most common cause of cancer-

related death in men and women, is responsible for 1.3 million deaths worldwide annually, as

of 2004[1]. The most common symptoms are shortness of breath, coughing (including

coughing up blood), and weight loss. Epidermal growth factor receptor (EGFR), a receptor

World Journal of Pharmaceutical ReseaRch

Volume 3, Issue 3, 4248-4262. Research Article ISSN 2277 – 7105

Article Received on 02 March 2014, Revised on 25 March 2014, Accepted on 18 April 2014

*Correspondence for

Author

Bhagavathi S

Research Scholar,

Department of

Biotechnology & Bio

Informatics Centre, Barkatullah University,

Bhopal-462026, India


4249


tyrosine kinase, is frequently over expressed in non-small cell lung cancer (NSCLC). These

receptors play an important role in tumor cell survival and activated phosphorylated EGFR

results in the phosphorylation of downstream proteins that cause cell proliferation, invasion,

metastasis, and inhibition of apoptosis. Expression appears to be dependent on histological

subtypes, most frequently expressed in squamous cell carcinoma but also frequently

expressed in adenocarcinomas and large cell carcinomas [2]. The protein and ligand

interaction takes an important part in protein function. Both ligand and its binding site are

essential components for understanding how the protein ligand complex functions. Most

cancers are highly invasive and there are problems of recurrence even after surgery,

chemotherapy and radiation treatment. MMPs are a family of highly homologous metal

dependent endopeptidases that can cleave most of the constituents of the extracellular matrix

such as collagen, fibronectin, laminin and elastin [3] and are inhibited by endogenous tissue

inhibitor of metalloproteinases (TIMPs) or synthetic inhibitors such as EDTA and

phenanthroline. Comprehension of the exact mechanisms involved in MMP activity has been

complicated by the differing expression patterns and roles of these proteases within the tumor

[4]. Further complicating the situation, these enzymes have overlapping substrate specificities

[5] creating difficulty in designing appropriate inhibitors for only one protease [6]. In

addition, the MMPs are present at globally low concentration, but they are concentrated on

the surface of cells at highly elevated and activated concentrations. Cancer usually is the

cause of the altered interaction between the multiple genes rather than changes in a single

causal gene [7] and the functional interactions predict the priority of the highly connected

nodes and its neighbors [8].

The first PLK was identified in Drosophila melanogaster (polo), with orthologs also found in

yeast (cdc5 and plo1) and Xenopus (Plx) [9-11]. Each of these PLK orthologs are essential

regulators of mitosis and are structurally and functionally related to the mammalian family

member PLK1. The mammalian family is comprised of three additional members PLK2,

PLK3, and PLK4. Like PLK1, PLK4 functions during mitosis, albeit in a different manner;

PLK2 and PLK3 have non mitotic roles in regulating the cell cycle [12]. The PLKs are highly

conserved serine/threonine kinases distinguished by noncatalytic C-terminal domains of 60–

70 amino acids termed the polo-box domain (PBD). The PBD serves as a binding module to

phosphorylated motifs on other proteins mediating protein-protein interactions [13] [14]. It

has emerged that additional functions for PLK1 outside of mitosis exist. These include the

possible involvement in the regulation of telomere stabilization, the regulation of DNA


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topoisomerase II, and DNA repair [15] [16] . Activity of PLK1 is inhibited in the presence of

DNA damage to ensure that these compromised cells do not progress into mitosis [17].

However following satisfaction or relaxation of the DNA damage checkpoint, PLK1 is

necessary to enable mitotic entry [18] .Small molecule inhibitors targeting the catalytic active

site of PLK1 are under evaluation in clinical trials for both solid and hematological

malignancies [19]. Polo Like Kinase 1 is the most investigated member of the family and has

been widely pursued as a cancer target because it is over expressed in several human tumor

types. PLK1 is over expressed in a broad spectrum of cancer types, and its expression often

correlates with poor patient prognosis [20]. Moreover, as PLK1 is associated with

tumorigenesis and belongs to a family of disease-relevant protein kinases that can be targeted

by different drugs, it represents a promising approach for the development of novel

anticancer therapies Numerous studies have been published examining the potential of PLK1

as an antitumor drug target, including work with antisense oligonucleotides, small interfering

(si) RNA and small molecules [21–23]. Clinical benefit has been observed for some tumor

types in Phase I and has warranted Phase II studies for both single agent as well as

combination trials. Thrombomodulin which is a receptor for thrombin on the surface of the

vascular endothelial cells neutralizes thrombin and the formed thrombin- TM complex

activates protein C. Thrombomodulin is not only a thrombin receptor but also an onco

developmental antigen, which is found in lung cancers [24][25]. TM expression in the lung

cancer cells appears to vary depending on the cellular conditions. It can be roughly

speculated that functionally active Thrombomodulin on lung cancer cells may modulate the

biological behaviors of these cells, such as invasiveness and metastatic potential. Lung cancer

patient’s specimens were analyzed by genome-wide microarray analysis for the gene that best

correlated with a poor prognostic factor of lung cancer. This analysis identified trophinin as

one of the best-correlated genes with BIRC5. Expression of trophinin protein in lung cancer

was confirmed by immunohistochemistry. The trophinin activity in cancer metastasis was

determined by either transfecting trophinin cDNA into lung cancer cells or by knockdown of

the endogenous gene with siRNA. Trophinin over expression increased cell invasiveness,

while knockdown inhibited it. The study suggests that trophinin is a prognostic factor for

early stage lung cancer. [26]


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MATERIALS AND METHODS

Target Structure prediction and Active site analysis

The 3-D crystal structure of the targeted lung cancer proteins are Polo Like Kinase 1,

Thrombomodulin, Trophinin and Matrix Metallo Proteinase was modeled using suitable

templates from the protein data bank (PDB) (www.rcsb.org/pdb). Structural and active site

studies of the protein were done by using Q site finder and visualized using Rasmol software.

Ligand preparation and optimization

Using Chemsketch Software the structures of the drugs and analogs were sketched and

generated their MOL File followed by subsequent generation of their 3-D structures by using

molecule format converter tool.

Docking using Autodock

The molecular docking was performed using Auto Dock; a suite of automated docking tools.

The software is used for modeling flexible small molecule such as drug molecule binding to

receptor proteins of known three dimensional structures. It uses Genetic Algorithms for the

conformational search and is a suitable method for the docking studies. The technique

combines simulated annealing for conformation searching with a rapid grid based method of

energy evaluation. Auto Dock tools is used to prepare, run and analyze the docking

simulations, in addition to modeling studies. Auto Dock is the most cited docking software

because it is very fast, it provides high quality predictions of ligand conformations and good

correlations between inhibition constants and experimental ones. During the docking

simulations, the inhibitors were regarded as flexible and subjected to an energy minimization.

The ligand orientations were scored through the use of a force-field-based energy scoring

function, and the top-scored binding structure was selected. [27][28].

RESULTS AND DISCUSSION

The key proteins that are responsible for Lung cancer are Polo Like Kinase 1,

Thrombomodulin, Trophinin and Matrix Metallo Proteinase. The three dimensional structure

of these proteins were modeled using relevant PDB template structures. The potential active

sites of these proteins were identified using Q-Site finder as follows:


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Active sites of polo like kinase 1

LEU59,GLY60,LYS61,CYS67,ALA80,LYS82,GLU101,HIS105,VAL114,LEU130,GLU131,LEU132,CYS133,ARG134,ARG135,ARG136,SER137,GLU140,GLY180,ASN181,PHE183,GLY193,ASP194,PHE195,VAL161,LEU162,CYS164,GLN165,LEU167,HIS168,VAL172,ILE173,HIS174,ARG175,ASP176,LEU177,PRO215,TYR217,ILE218,ALA219,PRO220,ALA221,PRO223,ARG232,LEU234

Active Sites of Thrombomodulin

GLU141,ASP145,GLY146,PHE147,LEU148,CYS149,GLU150,PHE151,VAL171,SER172,ILE173,ILE241,PRO245,GLN248,LEU255,GLN256,ALA257,GLY259,ARG260,THR263,TYR296,VAL323,ASN324,THR325


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Active Sites of Trophinin

VAL230, GLN231, LYS232, LYS233, ASP234, PRO235, LYS236, ASP237, TRP238, ALA239, VAL240, GLN241, TYR242, GLU247, MET248, GLU249, GLN48, ALA51, ASN52,VAL55,LYS56,ARG91,ALA92,TYR94,THR95,MET99,PHE100,ASP234,PRO235,LYS236,GLN251,ALA252

Active Sites of Matrix Metallo Proteinase

GLY179,ILE180,LEU181,ALA182,LEU214,THR215,HIS218 ,GLU 219, PRO 232 ,LYS

233,ALA234,VAL235 ,MET 236 ,PHE 237, PRO 238,THR 239,TYR 240 ,LYS

241,VAL243,PHE248,ARG249.

The vast literature review suggests specific drug targets against these proteins as Vorinostat,

Gemcitabine, Paclitaxel and Etoposide. PUBCHEM reveals the biophysical properties of

these compounds. Vorinostat has a Molecular Weight of 264.3202 [g/mol] with Molecular

Formula C14H20N2O3 ,XLogP3: 1.9,H-BondDonor:3,H-BondAcceptor:3 and has SMILES

notation as C1=CC=C(C=C1)NC(=O)CCCCCCC(=O)NO. Literature suggests the

application of vorinostat in treatment of advanced non-small-cell lung cancer (NSCLC) that

showed improved response rates and increased median progression free survival and overall

survival. Gemcitabine has a Molecular Weight of 263.198146 [g/mol] with Molecular


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Formula C9H11F2N3O4,XLogP3: -1.5,H-Bond Donor: 3,H-Bond Acceptor: 6 and has SMILES

notation as C1=CN(C(=O)N=C1N)C2C(C(C(O2)CO)O)(F)F. Combination of gemcitabine

and carboplatin has been found to be effective in treating several different types of cancer,

but most commonly used to treat lung cancer. Paclitaxel has a Molecular Weight of

853.90614 [g/mol] with Molecular Formula: C47H51NO14,XLogP3: 2.5,H-Bond Donor: 4,H-

Bond Acceptor: 14 and SMILES notation as CC1=C2C(C(=O)C3(C(CC4C

(C3C(C(C2(C)C)(CC1OC(=O)C(C(C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)

C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C. Paclitaxel is approved in the UK for

ovarian, breast and lung cancers and Kaposi's sarcoma.[29] It is recommended in NICE

guidance of June 2001 that it should be used for non small cell lung cancer in patients

unsuitable for curative treatment, and in first-line and second-line treatment of ovarian

cancer. Etoposide has Molecular Weight of 588.55658 [g/mol] with Molecular Formula

C29H32O13,XLogP3: 0.6,H-Bond Donor: 3,H-Bond Acceptor: 13 and has SMILES notation as

CC1OCC2C(O1)C(C(C(O2)OC3C4COC(=O)C4C(C5=CC6=C(C=C35)OCO6)C7=CC(=C(

C(=C7)OC)O)OC)O)O. Etoposide phosphate is an anticancer agent and it is known in the

laboratory as a topoisomerase inhibitor. It exploits the normal mechanism of action of the

enzyme topoisomerase II, which aids in DNA unwinding and by doing so causes DNA

strands to break. Cancer cells rely on this enzyme more than healthy cells, since they divide

more rapidly. It is used as a form of chemotherapy for cancers such as Ewing's sarcoma, lung

cancer, testicular cancer, lymphoma, non lymphocytic leukemia, and glioblastoma

multiforme. It is often given in combination with other drugs. SMILES notation was drawn

using ACD Chemsketch and converted in to three dimensional PDB format using Molecular

converter tool.

The 3D structures of these Lung Cancer proteins were docked with various inhibitors using

Autodock Software. From the docking studies, it has been identified that Polo Like Kinase 1,

Thrombomodulin, Trophinin, Matrix Metallo Proteinase has been inhibited well by four drug

compounds of the study.

The Key interacting sites of Polo like Kinase 1 are LYS61, HIS168, HIS174, ARG175,

LEU177, LYS178, GLY180, ASN181, ASP194, TYR217, ALA219. The active site is

docked with the four drug compounds. Polo Like Kinase 1 interacts with Gemcitabine

forming 6 Hydrogen bonds and binds strongly with a docking score of –7.98 Kcal/mol,

Paclitaxel formed 5 Hydrogen bonds with a docking score of –6.86 Kcal/mol, Vorinostat


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forming 1 Hydrogen bonds and docking score of –8.43 Kcal/mol, with Etoposide forming 4

Hydrogen bonds and docking score of –8.57 Kcal/mol. Therefore, it can be seen that

Gemcitabine is the most effective inhibitor of Polo like kinase 1.

Docking of Polo like Kinase 1 with potential inhibitors

POLO LIKE KINASE 1 GEMCITABINE DOCKING

SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM HIS174 LEU177 TYR217 ARG175 ARG175 ARG175

CG N N N

O O O O

-7.98

6

POLO LIKE KINASE 1 PACLITAXEL DOCKING

SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM GLY180 ASN181 LYS178 LYS61 LYS61

O OD1 NZ O

O O O O

-6.86

5

POLO LIKE KINASE 1 VORINOSTAT DOCKING

SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

ASP194 N O -8.43

1

POLO LIKE KINASE 1

ETOPOSIDE DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

HIS168 ALA219 ARG175 ARG175

NE2 N O

O O H

-8.57

4


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The Key interacting sites of Thrombomodulin are ALA168, VAL171, GLN256, ARG260,

THR296. Thrombomodulin interacts with Gemcitabine forming 3 Hydrogen bonds and

docking score of –8.33 Kcal/mol , Paclitaxel forming 1 Hydrogen bonds and docking score of

–7.69 Kcal/mol ,Vorinostat forming 2 Hydrogen bonds and docking score of –10.1 Kcal/mol,

Etoposide forming 2 Hydrogen bonds and docking score of –6.29 Kcal/mol . It is evident that

Vorinostat acts as better inhibitor against Thrombomodulin receptor.

Docking of Thrombomodulin with potential inhibitors

THROMBOMODULIN GEMCITABINE DOCKING SCORE

(Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

ARG260 GLN256 VAL171

N O O

O O H

-8.33

3

THROMBOMODULIN PACLITAXEL DOCKING SCORE

(Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

THR294 OG1 O -7.61 1

THROMBOMODULIN VORINOSTAT DOCKING

SCORE

(Kcal/mol)

H-

BONDS

RESIDUE ATOM ATOM

GLN256

GLN256 O O -10.1 2


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The Key interacting sites of Trophinin are ASN52, ARG91, TYR94, ASP234, LYS236,

LYS241, ALA 252. Trophinin interacts with Gemcitabine forming 1 Hydrogen bonds and

docking score of –6.8 Kcal/mol , Paclitaxel forming 7 Hydrogen bonds and docking score of

–10.6 Kcal/mol ,Vorinostat forming 7 Hydrogen bonds and docking score of –9.63 Kcal/mol

, Etoposide forming 3 Hydrogen bonds and docking score of –9.48 Kcal/mol . These results

suggest that Paclitaxel is effective against Trophinin forming a stable docked structure.

Docking of Trophinin with potential inhibitors

THROMBOMODULIN ETOPOSIDE DOCKING

SCORE

(Kcal/mol)

H-

BONDS

RESIDUE ATOM ATOM

GLN203

ALA168

O

O

O

O

-6.29

2

TROPHININ GEMCITABINE DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

LYS241

O

O

-6.8

1

TROPHININ PACLITAXEL DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM LYS236 LYS236 TYR94 ARG91 ARG91 ARG91 ALA 252

NZ OH NE O

O O O H

-10.6

7


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The Key interacting sites of Matrix Metallo Proteinase are LYS136, PRO232, ALA234,

ALA235, PHE237, THR239, LYS241, ARG249.The Matrix Metallo Proteinase interacts

with Gemcitabine forming 3 Hydrogen bonds and docking score of –8.4 Kcal/mol, Paclitaxel

forming 1 Hydrogen bonds and docking score of –8.49 Kcal/mol, Vorinostat forming 7

Hydrogen bonds and docking score of –11.1 Kcal/mol, Etoposide forming 2 Hydrogen bonds

and docking score of –9.29 Kcal/mol. Thus, Vorinostat effectively binds and inhibits Matrix

Metallo Proteinase class of proteins.

Docking of Matrix Metallo Proteinase with potential inhibitors

TROPHININ VORINOSTAT DOCKING

SCORE

(Kcal/mol)

H-

BONDS

RESIDUE ATOM ATOM

ASN52

ARG91

ASP234

ALA252

OD1

NH2

OD2

O

H

O

O

O

-9.63

7

TROPHININ ETOPOSIDE DOCKING

SCORE

(Kcal/mol)

H-

BONDS

RESIDUE ATOM ATOM

LYS236

ASP234

ASP234

HN

O

O

O

-9.48

3

MATRIX METALLO PROTEIN

GEMCITABINE DOCKING SCORE

(Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM ARG249 THR239 LYS241

O O O

N O O

-8.4 3


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These results suggest that all the four compounds are effective on their specific targets. The

result of Lipinski’s rule suggests that the drug targets are best therapeutic drugs. Docking

study and In silico toxicity results proves the application of compounds as Potential and

Natural Therapeutic agents to treat Lung Cancer.

CONCLUSION

The Protein-Ligand interaction plays a significant role in structural based drug designing.

Our approach in Molecular Docking analysis resulted in the identification of potential drug


PACLITAXEL DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

LYS136

O

H

-8.49

1


VORINOSTAT DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM ARG249(2) ALA235(2) PHE237(2) ALA234

O O O O

H N O O

-11.1

7


ETOPOSIDE DOCKING SCORE (Kcal/mol)

H-BONDS

RESIDUE ATOM ATOM

PRO232 ALA234

O O

H H

-9.29

2


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targets. In the present work we have taken the four key targets that play a crucial role in lung

cancer and identified the drugs that were used against Lung Cancer to study its efficacy.

From this study report we can conclude that some of the modified drugs are better than the

commercial drugs available in the market. These drugs can be tested in wet lab and research

and can be further validated for clinical trials. This study facilitates initiation of the drug

discovery process for Lung cancer to present the scientific community with better inhibitors

and /or drugs. In future, research work can be used further in clinical trials to test its

effectiveness and for social benefits thus reducing the time and cost in drug discovery

process.

ACKNOWLEDGEMENTS

As the Corresponding Author I’m thankful to my Guide Dr. Gulshan Wadhwa for guiding

and correcting various documents with attention & care and also thanks to Dr.Anil Prakash,

Barkatullah University, Bhopal, for extending his support.

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