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Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well-known carcinogens. We analyzed the interaction of enzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding was characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highest obtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol, -7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energy between NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83 kcal/mol and -7.67 kcal/mol respectively. In order to find out the effect of NNK and NNAL on enzymes involved in the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/ NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning of genes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of these genes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathways leading to damage buildup and finally contributing to cancer formation.
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Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 5311
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.13.5311
Binding Pattern of Cigarette Smoke Carcinogens NNK and NNAL with NER Pathway Enzymes: an Onco-informatics Study
Asian Pac J Cancer Prev, 16 (13), 5311-5317
Introduction
Lung cancers are powerfully linked with cigarette smoke
carcinogens like NNK (4-(Methylnitrosamino)-1-(3-
pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino)-
1-(3-pyridyl)-1-butan-1-ol) (Xue et al., 2014). One of
the preliminary critical actions is most likely damage
of the hereditary material (DNA) by a cigarette smoke
carcinogen. This damage can, beneath the denite status,
be repaired by cellular DNA repair mechanisms (Raphael
Ceccaldi et al., 2015). Though, if not repaired, cells will
try to duplicate their DNA during cell division, but are
obstructed by the damage and will do fault duplication
progression leading to gene mutations brought onto a
trail of uncontrolled cell division leading to a tumor
growth. Studies show that in ordinary cells, NER removes
numerous types of DNA lesions, defending cell integrity
(Rouillon et al., 2011).
However, in cancer cells uncovered to DNA
1Department of Health Information Management, College of Applied Medical Sciences, Buraydah Colleges, Al-Qassim-Buraydah
King Abdulaziz Road, East Qassim University, Buraydah, 5Research and Scientic Studies Unit, College of Nursing and Allied Health
Sciences, Jazan University, Jazan, Saudi Arabia, 2Environmental Carcinogenesis & Toxico-informatics Laboratory, Department
of Biosciences and Bioengineering, Integral University , Uttar Pradesh, 3Pharmaco-informatics Department, National Institute
of Pharmaceutical Education and Research (NIPER), 4BioMedical Informatics Centre, Rajendra Memorial Research Institute of
Medical Sciences (RMRIMS) Agam Kuan,Bihar, India. *For correspondence: mlohani@iul.ac.in
Abstract
Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNAL
(4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well-known carcinogens. We analyzed the interaction of
enzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding was
characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highest
obtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol,
-7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energy
between NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83
kcal/mol and -7.67 kcal/mol respectively. In order to nd out the effect of NNK and NNAL on enzymes involved
in the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/
NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning of
genes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of these
genes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathways
leading to damage buildup and nally contributing to cancer formation.
Keywords: NER pathway enzymes - NNK - NNAL - cigarette smoke carcinogens - docking
RESEARCH ARTICLE
Binding Pattern Elucidation of NNK and NNAL Cigarette
Smoke Carcinogens with NER Pathway Enzymes: an Onco-
Informatics Study
Qazi Mohammad Sajid Jamal1, Anupam Dhasmana2, Mohtashim Lohani2*,
Sumbul Firdaus2, Md Yousuf Ansari3,4, Ganesh Chandra Sahoo3,4, Shaul Haque5
damaging compounds that alter the DNA helix or
form unwieldy injuries to the genome, NER take part
in the managing the damage, consequently protecting
cancer cells from fatality (Nouspikel, 2009). But NNK
(4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and
NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-
ol) can alter the biological activity of NER repair enzymes.
Therefore, In order to execute our hypothesis, we have
selected 17 enzymes involved in NER pathways and
their interaction with cigarette smoke carcinogens NNK
(4-(Methylnitrosamino) -1-(3-pyridyl) -1-butanone) and
NNAL (4-(methylnitrosamino) -1-(3-pyridyl) -1-Butan-
1-ol). Molecular docking analyses were performed using
Autodock 4.2 tools. On the basis of obtaining top four
docking energies we have selected RAD23A, CCNH,
CDK7, and CETN2 genes for the further analysis to know
the effect of NNK/NNAL on the corresponding enzymes
function. The normal functioning of the selected enzymes
describes that RAD23A (UV excision repair protein
Qazi Mohammad Sajid Jamal et al
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015
5312
RAD23 homolog A) involved in nucleotide excision repair
and is thought to be functionally equivalent for RAD23B
in global genome nucleotide excision repair (GG-NER)
by association with XPC. Two human homologs of Rad23
are functionally interchangeable in complex formation and
stimulation of XPC repair activity (Sugasawa et al., 1997).
CCNH (cyclin H) regulates CDK7, the catalytic subunit
of the CDK-activating kinase (CAK) enzymatic complex.
CAK activates the cyclin-associated kinases CDK1,
CDK2, CDK4 and CDK6 by threonine phosphorylation.
CDK7 (Cyclin-dependent kinase 7) required for DNA-
bound peptides-mediated transcription and cellular growth
inhibition DNA-Bound peptides control the mRNA
transcription through CDK7 (Lu X et al., 2009) and
CETN2 (Centrin-2) Involved in global genome nucleotide
excision repair (GG-NER) by acting as a component of the
XPC complex. Cooperatively with RAD23B appears to
stabilize XPC. Centrosome protein centrin2/caltractin1 is
part of the xeroderma pigmentosum group C complex that
initiates global genome nucleotide excision repair (Araki
M et al., 2001;S.Matsumoto et al.,2015).
Computational tools such as molecular docking are
important to understand the binding capabilities of NNK
and NNAL with enzymes involved in NER pathways (Xia
et al., 2012). It has never been explored through in silico
approaches. Therefore, we used protein-protein docking
to know the functional loss of the enzymes due to their
interaction with NNK and NNAL. In order to perform
protein-protein interaction it is necessary to nd out the
co-operated functional enzymes encoded by genes using
STRING 9.0.5 database (Szklarczyk et al., 2011) and their
3D structures. At last the comparative analysis (Protein-
Protein docking vs Protein- Complex*) was completed
by ZDOCK protocol using Discovery Studio Client 2.5
(Accelrys Software Inc, 2013).
Materials and Methods
Preparation of ligand structures
Ligand le of NNK (4-(Methylnitrosamino)-1-(3-
pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino)-
1-(3-pyridyl)-1-butan-1-ol) were downloaded in .mol
format (Figure: 1 and Figure: 2) from ChemSpider
Chemical Database (Harry et al., 2010). These les could
not directly use by Autodock 4.2 tools (Morris et al., 2009)
thus; we have to convert it into .pdb les and also further
the ligands were submitted for CHARMm (Brooks et al.,
1983; 2009) energy minimization protocol in Discovery
Studio Client 2.5.
Preparation of protein structures
The structures of enzymes involved in the NER
pathways were obtained from Protein Data Bank (Berman
et al., 2000) (Table 1). Published structures were edited to
remove HETATM and water molecule using Discovery
Studio Client 2.5. Energy minimization was performed
by the implementation of CHARMm force eld (D.T
Mirijanian et al., 2014) after addition of hydrogen atoms
to the selected enzymes using Accelyrs Discovery studio
client 2.5.
Docking studies
Molecular Docking studies were performed to analyze
the binding afnity of NNK/NNAL with enzymes involved
NER pathways. Autodock (Version 4.2) suite (Morris et
al., 1998; 2009) and Cygwin interface was used in the
Microsoft Windows 7 professional, operating System
on Intel® Xeon® Processor E3-1220 v3 (Quad Core,
3.10GHz Turbo, 8MB) and 256GB 2.5inch Serial ATA
Solid State Drive of Dell Precision T1700 Workstation
was used to dock the NNK/NNAL on binding site of
the enzymes. Molecular docking methods followed by
the searching the best conformation of enzymes and
carcinogens complex on the basis of binding energy.
Water molecules were removed from the 3D X-ray
crystallography structures of enzymes before docking
and hydrogen atoms were added to all target enzymes.
Kollman united charges and salvation parameters were
added to the enzymes. Gasteiger charge was added to the
ligands. Grid box was set to cover the maximum part of
enzymes and ligands. The values were set to 60×60×60 Å
in X, Y and Z axis of a grid point. The default grid points
spacing was 0.375 Å. Lamarckian Genetic Algorithm
(LGA) (Goodsell et al., 1996; Tsai et al., 2012) was used
for enzymes-ligands exible docking calculations. The
LGA parameters like population size (ga_pop_size),
energy evaluations (ga_num_generation), mutation rate,
crossover rate and step size were set to 150, 2500000,
27000, 0.02, 0.8 and 0.2 Å, respectively. The LGA runs
were set at 50 runs. All obtained conformations of enzymes
and ligand complex were analyzed the interactions and
binding energy of the docked structure using Discovery
Studio 2.5 molecular visualization software.
Protein-protein interaction analysis
We found the interacting proteins (used as ligands)
of selected enzymes using STRING 9.0.5 database
that predict interacting interactions incorporate direct
(physical) and indirect (functional) associations derived
Figure 1. 4-(Methylnitrosamino)-1-(3-pyridyl)-
1-butanone, PubChem Compound ID- 47289,
ChemSpider ID 43038
Figure 2. 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butan-1-ol, PubChem Compound ID- 104856,
ChemSpider ID- 94646dd
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 5313
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.13.5311
Binding Pattern of Cigarette Smoke Carcinogens NNK and NNAL with NER Pathway Enzymes: an Onco-informatics Study
from four sources, i.e. genomic context, high throughput
experiments (conserved) co-expression and previous
knowledge of proteins against your query (Figure:5 A,B,C
and D). We used discovery studio Client 2.5 for Zdock
(Dock Proteins) Protocol. Zdock scores obtained for
both Protein-Protein interactions as well as for Protein-
Complex (ligand protein+NNK/NNAL) interaction.
Z dock calculations
Discovery studio Client 2.5 was used to complete
protein-protein docking using ZDOCK is an initial
stage, rigid body molecular docking algorithm that uses
a fast Fourier transform (FFT) algorithm to improve
performance for searching in translational space (Chen et
al., 2003; Pierce et al., 2014). All of the available structures
from PDB were used to calculate the docking poses and the
structures obtained were subjected to energy minimization
using the smart minimize algorithm (Max steps 200, RMS
gradient 0.01) in the program Discovery studio 2.5. The
resulting Zdock scores with the highest value were used
as appropriate conformational pose (Jamal et al., 2012).
Results and Discussion
In the achievement of the current investigation
molecular docking techniques were adopted to explore
the binding capabilities of NNK and NNAL with enzymes
encoded by respective genes of NER pathways. Primarily
the 1IRD (Crystal Structure of Human Carbonmonoxy-
Haemoglobin at 1.25 Å Resolution) was used as a positive
control and 3CI9 (Human heat shock factor-binding
protein 1) as a negative control to validate our docking
analysis. Molecular interaction results of these enzymes
showed that 1IRD docked with NNK, observed binding
energy was -6.68 Kcal/Mol, it docked with NNAL and
observed binding energy was -6.31 Kcal/Mol. 3CI9
docked with NNK with the experimental binding energy
of -3.91 Kcal/Mol, it interacted with NNAL with binding
energy of +2.09 Kcal/Mol. We performed docking analysis
between 16 enzymes and NNK/NNAL separately. The
observed docking energy between NER pathway enzymes
and NNK were ranging from -4.28 kcal/mol to -8.05 kcal/
mol (Table 1) similarly between NER pathways enzymes
and NNK were ranging from -5.33 kcal/mol to -7.94 kcal/
mol. In the completion of next step of our hypothesis, we
selected top four NER enzymes encoded by respective
genes from Table 1 and Table 2 on the basis of their highest
obtained docking energy between NNK and enzymes
RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/
mol, -7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol
respectively. Similarly the highest obtained docking
energy between NNAL and enzymes RAD23A, CCNH,
CDK7, and CETN2 are -7.46 kcal/mol, -7.94 kcal/mol,
-7.83 kcal/mol and -7.67 kcal/mol respectively (Table 1).
The active site characterization analysis of top four
enzymes revealed that NNK and NER enzymes shown that
RAD23A involved in the building of 2 hydrogen bonds
A: GLN21:HE21 - :UNK0:N4 and A: GLN21:HE21 -
:UNK0:O2 with the distance of 2.40437 Å and 1.8656
Å respectively with NNK. The hydrophobic pocket
characterized by the occurrence of Phe14, Ser17, Leu18,
Gln21, Ala22, Phe36, Leu37, Leu38, Gln40, Asn41,
Phe42, Asp43 amino acid residues. The estimated
inhibition constant of NNK and RAD23A docked
complex was 112.03 (Table 2 Figure: 3 A). The CCNH
involved in the building of 2 hydrogen bonds A: ASP202:
HN - :UNK0:N4 and A: ASP202: HN - :UNK0:O2 with
the distance of 2.32473 Å and 1.94374 Å, respectively
with NNK. The hydrophobic pocket characterized by
the occurrence of Arg23, Met54, Cys57, Lys58, Glu61,
Phe87, Lys88, Tyr91, Leu200, Thr201, Asp202, Leu205,
Leu258, Lys261, and Tyr262 amino acids residues. The
estimated inhibition constant of NNK and CCNH docked
complex was 91.24 uM (Table 2 Figure: 3 B). The CDK7
involved in building of 5 hydrogen bonds A: LYS139:HZ3
- :UNK0:O1, A: ASN142:HD22 - :UNK0:O1, A: SER161:
HN - :UNK0:O2, A: SER161: HG - :UNK0:N4 and A:
SER161: HG - :UNK0:O2 with distance of 1.67265
Å, 2.2816 Å, 2.05534 Å, 1.8268 Å and 2.24771 Å
respectively.The hydrophobic pocket characterized by
the occurrence of Gly21, Gln22, Phe23, Lys41, His135,
Asp137, Lys139, Asn142, Ala154, Asp155, Phe156,
0
25.0
50.0
75.0
100.0
Newly diagnosed without treatment
Newly diagnosed with treatment
Persistence or recurrence
Remission
None
Chemotherapy
Radiotherapy
Concurrent chemoradiation
10.3
0
12.8
30.0
25.0
10.1
6.3
51.7
75.0
51.1
30.0
31.3
46.8
56.3
27.6
25.0
33.1
30.0
31.3
38.0
31.3
Table 1. NNK and NNAL Docked with EnzymesInvolved in NER Pathway
S. No. Gene’s Name PDB ID Accession Code GenBank Uniprot Docking Energy
(vdW + Hbond + desolv Energy )
Docked with NNK Docked with NNAL
1. RPA2 1DPU NM_002946 NP_002937 P15927 -6.53 kcal/mol -6.19 kcal/mol
2. RAD23A (HR23A) 1DV0 NM_005053 NP_005044 P54725 -7.13 kcal/mol -7.46 kcal/mol
3. MT1 1G25 NM_002431 NP_002422 P51948 -6.06 kcal/mol -5.98 kcal/mol
4. CCNH 1KXU NM_001239 NP_001230 P51946 -7.27 kcal/mol -7.94 kcal/mol
5. RAD23B (HR23B) 1P1A NM_002874 NP_002865 P54727 -6.46 kcal/mol -7.01 kcal/mol
6. CDK7 1UA2 NM_001799 NP_001790 P50613 -8.05 kcal/mol -7.83 kcal/mol
7. LIG1 1X9N NM_000234 NP_000225 P18858 -6.88 kcal/mol -7.46 kcal/mol
8. XPA 1XPA NM_000380 NP_000371 P23025 -6.99 kcal/mol -6.82 kcal/mol
9. GTF2H2 1Z60 NM_001515 NP_001506 Q13888 -6.74 kcal/mol -7.43 kcal/mol
10. CETN2 1ZMZ NM_004344 NP_004335 P41208 -7.58 kcal/mol -7.67 kcal/mol
11. ERCC1 2A1I NM_001983 NP_973730 Q7Z7F5 -6.74 kcal/mol -6.54 kcal/mol
12. ERCC4 (XPF) 2AQ0 NM_005236 NP_005227 Q92889 -6.41 kcal/mol -6.23 kcal/mol
13. GTF2H5 (TTDA) 2JNJ NM_207118 NP_997001 Q6ZYL4 -6.27 kcal/mol -5.33 kcal/mol
14. XPC 2OBH NM_000380 NP_000371 P23025 -6.25 kcal/mol -6.08 kcal/mol
15. GTF2H1 2RNR NM_005316 NP_005307 P32780 -6.46 kcal/mol -5.83 kcal/mol
16. ERCC3 (XPB) 4ERN NM_000122 NP_000113 P19447 -4.28 kcal/mol -5.56 kcal/mol
Qazi Mohammad Sajid Jamal et al
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015
5314
Table 2. Docking Studies of NNK and NER Pathways Enzymes Interaction
S.No. Enzymes PDB ID H-Bonds H-Bonds
Distance
(Å)
Residues involved in Hydrophobic
region
Docking En-
ergy (vdW +
Hbond + de-
solv Energy )
kcal/mol
Inhibition
Constant
(uM)
1. RAD23A
(HR23A)
1DV0 A:GLN21:HE21 -
:UNK0:N4
2.40437 -7.13 112.03
A:GLN21:HE21 -
:UNK0:O2
1.8656 Phe14,Ser17,Leu18,Gln21,Ala22,
Phe36,Leu37,Leu38,Gln40,Asn41,
Phe42,Asp43
2. CCNH 1KXU A:ASP202:HN -
:UNK0:N4
2.32473 -7.27 91.24
31 Arg23,Met54,Cys57,Lys58,Glu61
,Phe87,Lys88,Tyr91,Leu200, Thr
201,Asp202,Leu205,Leu258,Lys2
61,Tyr262
A:ASP202:HN -
:UNK0:O2
1.94374
3. CDK7 1UA2 A:LYS139:HZ3 -
:UNK0:O1
1.67265 -8.05 26.15
A:ASN142:HD22
- :UNK0:O1
2.26816 Gly21,Gln22,Phe23,Lys41,His135
,Asp137,Lys139,Asn142,Ala154,A
sp155,Phe156,Gly157,Lys160,Ser
161,Phe162,Thr175
A:SER161:HN -
:UNK0:O2
2.05534
A:SER161:HG -
:UNK0:N4
1.8268
A:SER161:HG -
:UNK0:O2
2.24771
4. CETN2 1ZMZ A:ARG18:HN -
:UNK0:N4
2.231 -7.58 49.61
A:ARG18:HN -
:UNK0:O2
1.7428 Gln15,Arg16,Lys17,Arg18,Met19,
Leu25,Gln29,Lys30,Gln31,Ile33,A
rg34,Phe86,Leu90
A:MET19:HN -
:UNK0:O2
1.87497
A:LYS30:HZ2 -
:UNK0:O1
2.09563
Figure 3. (A) 1DV0 (RAD23A (HR23A)) Docked with
NNK (in Purple color) (B) 1KXU (CCNH) Docked with
NNK (C) 1UA2 (CDK7) Docked with NNK ( D) 1ZMZ
(CETN2) Docked with NNK (in Purple color) and the
Hydrogen Bonds Shown by Green Dotted Lines. All
graphics generated by discovery studio visualizer
A B
C D
A B
C D
Figure 4. (A) 1DV0 (RAD23A (HR23A)) Docked with
NNAL (in Purple color) (B) 1KXU (CCNH) Docked
with NNAL C 1UA2 (CDK7) Docked with NNAL (D)
1ZMZ (CETN2) Docked with NNAL (in Purple color)
and Hydrogen Bonds Shown by Green Dotted Lines.
All graphics generated by discovery studio visualizer
A
B
C D
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 5315
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.13.5311
Binding Pattern of Cigarette Smoke Carcinogens NNK and NNAL with NER Pathway Enzymes: an Onco-informatics Study
Gly157, Lys160, Ser161, Phe162, and Thr175 amino
acids residues. The estimated inhibition constant of
NNK and CDK7 docked complex was 26.15 uM (Table
2 Figure:3 C). The CETN2 involved in the building of 4
hydrogen bonds A: ARG18: HN - :UNK0:N4, A: ARG18:
HN - :UNK0:O2, A: MET19: HN - :UNK0:O2, and A:
LYS30:HZ2 - :UNK0:O1 with the distance of 2.231 Å,
1.7428 Å, 1.87497 Å and 2.09563 Å respectively. The
hydrophobic pocket characterized by the occurrence
of Gln15, Arg16, Lys17, Arg18, Met19, Leu25, Gln29,
Lys30, Gln31, Ile33, Arg34, Phe86, and Leu90 amino
acids residues. The estimated inhibition constant of NNK
and CETN2 docked complex was 46.61 uM (Table 2
Figure: 3 D).
Furthermore, the active site characterization analysis
of top four enzymes also revealed that NNAL and NER
Table 3. Docking Studies of NNAL and NER Pathways Enzymes Interaction
S.No. Enzymes PDB ID H-Bonds H-Bonds
Distance
( Å)
Residues involved in
Hydrophobic region
Docking En-
ergy (vdW +
Hbond + de-
solv Energy)
kcal/mol
Inhibition
Constant
(uM)
1. RAD23A 1DV0 A:GLN21:HE21
- :UNK0:O2
2.07489 Phe14,Leu18,Gln21,Ala22,Phe36, -7.46 kcal/
mol
67.58 uM
A:ASN41:HD21
- :UNK0:N4
2.18982 Leu37,Gln40,Asn41,Phe42,Asp43
: UNK0:H24 - A:
PHE42: O
2.03172
2. CCNH 1KXU A:LYS88:HZ2 -
:UNK0:O1
2.26011 Arg23,Met54,Cys57,Lys58,Glu61, -7.94 kcal/
mol
29.57 uM
A:ASP202:HN -
:UNK0:N5
2.14097 Phe87,Lys88,Tyr91,Leu92,Leu200,
A:ASP202:HN -
:UNK0:O2
2.16487 r201,Asp202
:UNK0:H24 -
A:GLU61:OE1
1.85083 Leu205,Leu258,Tyr262
3. CDK7 1UA2 A:LEU138:HN -
:UNK0:N5
1.96313 His135,Arg136,Asp137,Leu138,L
ys139,
-7.83 kcal/
mol
39.55 uM
A:LEU138:HN -
:UNK0:O2
2.04471 Phe162,r175,Arg176,Tyr178,A
rg179
:UNK0:H24 -
A:ASP137:OD1
1.84497 Leu183,Val194,Ala198
:UNK0:N5 -
A:LEU138:O
3.00052
:UNK0:N5 -
A:TYR178:O
3.13345
4. CETN2 1ZMZ A:ARG18:HN -
:UNK0:N5
2.0811 Arg16,Lys17, Arg18,Met19,Leu25 -7.67 kcal/
mol
43.67 uM
A:ARG18:HN -
:UNK0:O2
2.14078 Gln29,Lys30,Ile33,Arg34,Phe86,
A:MET19:HN -
:UNK0:N5
1.87932 Leu90
A:MET19:HN -
:UNK0:O2
2.17551
A:LYS30:HZ2 -
:UNK0:O1
1.84969
:UNK0:H24 -
A:MET19:O
2.41349
enzymes shown that RAD23A involved in the building
of 3 hydrogen bonds A: GLN21:HE21 - :UNK0:O2,
A: ASN41:HD21 - :UNK0:N4, and: UNK0:H24 - A:
PHE42: O with the distance of 2.26011 Å, 2.18982 Å,
and 2.03172 Å respectively. The hydrophobic pocket
characterized by the occurrence of Phe14, Leu18, Gln21,
Ala22, Phe36, Leu37, Gln40, Asn41, Phe42, and Asp43
amino acid residues. The estimated inhibition constant
of NNAL and RAD23A docked complex was 67.58 uM
(Table 3 Figure: 4 A). The CCNH involved in the building
of 4 hydrogen bonds A: LYS88:HZ2 - :UNK0:O1, A:
ASP202: HN - :UNK0:N5, A: ASP202: HN - :UNK0:O2,
and: UNK0:H24 - A: GLU61:OE1 with the distance
of 2.26011 Å, 2.14097 Å, 2.16487 Å and 1.85083 Å,
respectively. The hydrophobic pocket characterized by
the occurrence of Arg23, Met54, Cys57, Lys58, Glu61,
Qazi Mohammad Sajid Jamal et al
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015
5316
0
25.0
50.0
75.0
100.0
Newly diagnosed without treatment
Newly diagnosed with treatment
Persistence or recurrence
Remission
None
Chemotherapy
Radiotherapy
Concurrent chemoradiation
10.3
0
12.8
30.0
25.0
20.3
10.1
6.3
51.7
75.0
51.1
30.0
31.3
54.2
46.8
56.3
27.6
25.0
33.1
30.0
31.3
23.7
38.0
31.3
0
25.0
50.0
75.0
100.0
Newly diagnosed without treatment
Newly diagnosed with treatment
Persistence or recurrence
Remission
None
Chemotherapy
Radiotherapy
Concurrent chemoradiation
10.3
0
12.8
30.0
25.0
20.3
10.1
6.3
51.7
75.0
51.1
30.0
31.3
54.2
46.8
56.3
27.6
25.0
33.1
30.0
31.3
23.7
38.0
31.3
Phe87, Lys88, Tyr91, Leu92, Leu200, Thr201, Asp202,
Leu205, Leu258, and Tyr262. The estimated inhibition
constant of NNAL and CCNH docked complex was
29.57 uM (Table 3 Figure: 4 B). The CDK7 involved
in the building of 5 hydrogen bonds A:LEU138:HN -
:UNK0:N5, A:LEU138:HN - :UNK0:O2, :UNK0:H24
- A:ASP137:OD1, :UNK0:N5 - A:LEU138:O, and
:UNK0:N5 - A:TYR178:O with the distance of 1.96313
Å, 2.04471 Å, 1.84497 Å, 3.00052 Å, and 3.13345 Å
respectively. The hydrophobic pocket characterized by the
occurrence of His135, Arg136, Asp137, Leu138, Lys139,
Phe162, Thr175, Arg176, Tyr178, Arg179, Leu183,
Val194, and Ala198 amino acid residues. The estimated
inhibition constant of NNAL and CDK7 docked complex
was 39.55 uM (Table 3 Figure: 4 C). CETN2 involved
in the building of 6 hydrogen bonds A:ARG18:HN -
:UNK0:N5, A:ARG18:HN - :UNK0:O2, A:MET19:HN
- :UNK0:N5, A:MET19:HN - :UNK0:O2, A:LYS30:HZ2
- :UNK0:O1, and :UNK0:H24 - A:MET19:O with the
distance of 2.0811 Å, 2.14078 Å, 1.87932 Å, 2.17551 Å,
1.84969 Å, and 2.41349 Å respectively. the hydrophobic
pocket characterized by the occurrence of Arg16, Lys17,
Arg18, Met19, Leu25, Gln29, Lys30, Ile33, Arg34, Phe86,
and Leu90 amino acids residues. The estimated inhibition
constant of NNAL and CETN2 complex was 43.67 uM
(Table 3 Figure: 4 D).
In the further analysis, the protein-protein docking
was adopted using ZDOCK protocol in Discovery Studio
Client 2.5. Initially, we have found out the cooperated the
enzymes encoded by genes for four selected enzymes,
i.e. RAD23A, CCNH, CDK7, and CETN2 by STRING
9.0.5 database. The found Best closely related enzymes
for RAD23A PDB ID: 1DV0 (RAD23 Homolog A) was
PDB ID: 2KDE (PSMD4 MCB1, 26S proteasome non-
ATPase regulatory subunit 4), for CCNH PDB ID: 1KXU
(CDK-Activating Kinase Complex Subunit) was PDB ID:
1UA2 (CDK7,Cell division protein kinase 7), for CDK7
PDB ID: 1UA2 (Cyclin H) was PDB ID: 1KXU (CDK-
Activating Kinase Complex Subunit) and for CETN2 PDB
ID:1ZMZ (Centrin, EF-Hand Protein, 2) was PDB ID:
2GGM (XPC, DNA-repair protein complementing XP-C
cells) (Figure 5 A, B, C and D). Later on we run ZDOCK
program for Protein-Protein Docking vs Protein-Complex
docking analysis.
The obtained Zdock scores 1DV0 vs 2KDV was 14.58,
1DV0+NNK vs 2KDE was 13.74, 1KXU vs 1UA2 was
14.24,1KXU+NNK vs 1UA2 was 13.08, 1UA2 vs 1KXU
was 14.96, 1UA2+NNK vs 1KXU was 13.08, 1ZMZ vs
2GGM was 15.92 and 1ZMZ+NNK vs 2GMM was 15.40
(Table 4).Similarly, obtained Zdock scores 1DV0 vs 2KDV
was 14.58, 1DV0+NNAL vs 2KDE was 13.76, 1KXU vs
1UA2 was 14.24,1KXU+NNAL vs 1UA2 was 13.84,
1UA2 vs 1KXU was 14.96, 1UA2+NNAL vs 1KXU was
13.68, 1ZMZ vs 2GGM was 15.92 and 1ZMZ+NNAL vs
2GMM was 15.55 (Table 4). The results shown that Zdock
score of protein complex (contain enzymes and cigarette
smoke carcinogens conformation) interaction were higher
than protein-protein interaction. Analysis clearly revealed
that when NNK/NNAL interacts with NER enzymes their
metabolic activity to form complex with its cooperated
enzymes reduces signicantly. Thus, NNK and NNAL
were capable to damage the DNA repair machinery and its
will lead to the functional loss of NER enzymes encoded
by genes RAD23A, CCNH, CDK7, and CETN2.
Figure 5. (A) CCNH Interacted with CDK7 (B) CDK7
Interacted with CCCNH (C) CETN2 Interacted
with XPC (D) RAD23A Interacted with PSMD4. All
interaction networks of selected enzymes obtained from
STRING database
A B
C D
Table 4. NNK and NNAL Binding to the Enzymes Reduces their Normal Functions after Analyzing the ZDOCK
Scores
S.
No.
Selected
Genes
PDB ID Interacted
enzymes
PP interaction of NNK
with enzymes
ZDOCK
Score
PP interaction of NNAL
with enzymes
ZDOCK
Score
(Obtained from
STRING 9.0.5)
NNK NNAL
1. RAD23A
(HR23A)
1DV0 2KDE 1DV0 vs 2KDE 14.58 1DV0 vs 2KDE 14.58
1DV0+NNK vs 2DKE 13.74 1DV0+NNAL vs 2DKE 13.76
2. CCNH 1KXU 1UA2 1KXU vs 1UA2 14.24 1KXU vs 1UA2 14.24
1KXU+NNK vs 1UA2 13.08 1KXU+NNAL vs 1UA2 13.84
3. CDK7 1UA2 1KXU 1UA2 vs 1KXU 14.96 1UA2 vs 1KXU 14.96
1UA2+NNK vs 1KXU 13.08 1UA2+NNAL vs 1KXU 13.68
4. CETN2 2GGM 1ZMZ vs 2GGM 15.92 1ZMZ vs 2GGM 15.92
1ZMZ 1ZMZ+NNK vs 2GMM 15.4 1ZMZ+NNAL vs 2GMM 15.55
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 5317
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.13.5311
Binding Pattern of Cigarette Smoke Carcinogens NNK and NNAL with NER Pathway Enzymes: an Onco-informatics Study
Conclusion
This hypothesis able to provide better understanding
to explore the molecular interaction of NNK and NNAL
with enzymes involved in NER pathways. It is also helpful
to understand the biological insights of NNK and NNAL
binding efcacy in the progression of cancer. The study
revealed that the enzymatic activity of these enzymes
RAD23A, CCNH, CDK7, and CETN2 affected by NNK
and NNAL. Therefore, the possibility of DNA damage will
be increased because these enzymes have an important
role in the DNA damage control. Once the DNA repair
machinery altered due to interaction of cigarette smoke
carcinogens NNK and NNAL the whole biological process
will lead to uncontrolled tumor growth and nally cancer
will be developed. For the further conrmation of study
the in vivo and in vitro validation needed.
Acknowledgements
The authors are thankful to College of Applied Medical
Sciences, Buraydah Colleges, Al Qassim, Saudi Arabia
for providing necessary infrastructure facility to complete
the study.
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