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402Copyright © All rights are reserved by Sameer.
Drug Designing & Intellectual Properties International
Journal
Research ArticleISSN: 2637-4706
Identification of Sirtuin Drug Targets (Homosapiens) For Lung
Cancer-Molecular Docking and ADME Analysis
Sameer* and Sudhakar Malla
Department of Biotechnology, Indian Academy Degree College,
Bangalore
*Corresponding author: Sameer, Department of Biotechnology,
Indian Academy Degree College, Bangalore
Received: April 25, 2020 Published: May 20, 2020
DOI: 10.32474/DDIPIJ.2020.03.000168
AbstractThe objective of this study was to investigate the
specific drug targets (Sirtuin 1,2,3,4,5, and 6) for lung cancer
employing
molecular docking simulation and ADME analysis against
Sinapaldehyde. The three-dimensional structure of the protein was
retrieved from Protein Data Base and of the ligand from Pubchem
database. Molecular docking simulation of the compounds was
performed using Ligpep 2.3, Schrodinger Suite 2009. In the present
study, drug likeness analysis was performed through Lipinski filter
& Admesar analysis using Swissadme online server and none of
the compounds breached Lipinski’s and ADME parameters, making them
prominent agents for bio-activities. And the outcome represents the
compounds (Sinapaldehyde) possibly serve as for the cure of lung
cancer.
Keywords: Sirtuin; Sinapaldehyde; Molecular docking; Lipinski;
ADME analysis, Anti-cancer
Introduction Lung cancer is the prominent source of cancer
associated death
across the world with a survival rate of 20% [1]. Lung cancer
can be differentiated into small cell lung cancer and non-small
cell lung cancer [2]. In the earlier decades, a huge number of
metabolic pathways like EGFR (Epidermal Growth Factor Receptor)
signaling pathway have been observed in the carcinogenesis family
indulging lung cancer & are used as specific targets in drug
development [3,4]. Sirtuins are group of proteins homologous to
yeast regulator (Sir 2) that was identified in 1984 as a gene
obligatory for continuing silent chromatin in yeast [5]. Sirtuins
family of proteins also came out to play a major role in various
pathological & physiological processes. Sirtuins genes
(SIRT1-7), in mammals [6,7]. Sirtuins genes are basically classes
of proteins which acquire nicotinamide adenine dinucleotide
(NAD+)-dependent deacetylase (SIRT1, SIRT2, SIRT3, SIRT5, SIRT6,
and SIRT7) and monoribosytransferase (SIRT4, and SIRT6) activities
[8-15]. Except SIRT5, all mammalians Sirtuins have been noted to be
indulged in cancer development but the roles of Sirtuins proteins
in cancer are very complex and attribute to cancer cells promotion
or suppression [16]. The selected ligand was recognized for
prediction against novel targets and predicted to interact with
Sinapaldehyde also called (E)-3-(4-hydroxy-
3,5-dimethoxyphenyl)-2-propenal, representative of the class of
compounds called as methoxyphenols which are water-insoluble and a
very weak compound (Table 1). (acidic in nature). During lignin
biosynthesis in Arabidopsis thaliana, an enzyme called
dihydroflavonol-4-reductase utilizes NADPH & Sinapaldehyde to
generate sinapyl alcohol & NADP+ (Figure 1). In the present
study, comparative investigation of the specific human sirtuin
proteins was carried out using molecular docking techniques which
identified the drug likeness of the respective ligand.
Figure 1: Sinapaldehyde.
https://lupinepublishers.com/index.phphttps://lupinepublishers.com/drug-designing-journal/http://dx.doi.org/10.32474/DDIPIJ.2020.03.000168
-
Citation: Sameer, Sudhakar Malla. Identification of Sirtuin Drug
Targets (Homosapiens) For Lung Cancer-Molecular Docking and ADME
Analysis. Drug Des Int Prop Int J 3(4) - 2020. DDIPIJ.MS.ID.000168.
DOI: 10.32474/DDIPIJ.2020.03.000168.
Volume 3 - Issue 4 Copyrights@ Sameer, et al.Drug Des Int Prop
Int J
403
Table 1: Activities and Functions of Target Human sirtuin
proteins.
Human Sirtuins Substrates Location(intracellula) Activity or
Action Function
SIRT1 AceCS1, APE1,beta-catenin Cytoplasm and nucleus
Deacetylase Metabolism inflammation
SIRT2 CDH1, CDC20, FOXO1, p300 Cytoplasm & nucleus
Deacetylase Cell cycle exit, adipocyte differentiation
SIRT3 AceCS2, GDH, LCAD, LKB1 Mitochondria Deacetylase Enhance
enzyme activity & promotes AceCS2 activity
SIRT4 GDH, MCD Mitochondria Transferase Reduction of GDH
activity & inhibits the activity of MCD.
SIRT5 CPS1, pyruvate & succinate dehydrogenase
MitochondriaDesuccinylase &
deacetylase Cellular respiration
SIRT6 CtlP, GCN5, H3K9 Nucleus Transferase &
deacetylasePromotes DNA end resection and
genome stability
Methodology Active binding site
The 3D structure of sirtuin (1, 2, 3, 4, 5, and 6) proteins
(PDBID: 4kxq.1.B, 1j8f.1.A, 4bn5.1.A, 5oj7.1.A, 5bwl.1.A, 3pki.1.A)
was build using SWISS-MODEL. Recognition of protein binding sites
were identified by FT site server and Pro-Bis server [17].
Recognition of binding site has a broad range of pertinences which
indulges functional relationships between proteins, structure-based
prediction, and drug design. And FT site server also exposed a
specific method for protein binding identification [18].
Ligand formation
Ligands are tiny molecules which bind to the Protein’s binding
sites. Sinapaldehyde structure obtained from Pubchem database
[19]. The compounds were converted to three-dimensional
structure with the help of PyMol version 1.3 [20]. And
physic-chemical properties of the ligands are measured by Pubchem
database.
Study of drug likeness of ligands
Lipinski filter were used for ligand prediction, according to
drug likeness criteria namely cLogP, hydrogen donor and acceptor,
molecular mass & molar refractive index [21]. SWISS-ADME was
used as convenient tool in drug investigation [22] and ligand
properties with respect to adsorption, distribution, metabolism,
and excretion (ADME). BOILED-EGG (Brain or Intestinal Estimated
permeation method) is approached as an accurate model that works
properly by computing the polarity of tiny molecules [23].
Molecular docking simulation
Figure 2: Cartoon representation of Sirtuin proteins (1,
2,3,4,5, and 6).
http://dx.doi.org/10.32474/DDIPIJ.2020.03.000168
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Citation: Sameer, Sudhakar Malla. Identification of Sirtuin Drug
Targets (Homosapiens) For Lung Cancer-Molecular Docking and ADME
Analysis. Drug Des Int Prop Int J 3(4) - 2020. DDIPIJ.MS.ID.000168.
DOI: 10.32474/DDIPIJ.2020.03.000168.
Volume 3 - Issue 4 Copyrights@ Sameer, et al.Drug Des Int Prop
Int J
404
The purpose of molecular docking is to assume or predict the
binding aspects of ligand and identify the orientation of molecule
with respect to active site. In docking method, all the binding
poses of molecules innards the catalytic site of an enzyme is being
concluded. After that, preparation of protein of the specific
target
sirtuin proteins 1,2,3,4,5,and 6 (PDB ID: 4kxq.1.B, 1j8f.1.A,
4bn5.1.A, 5oj7.1.A, 5bwl.1.A, 3pki.1.A) was performed with
employing Protein preparation wizard of Schrodinger 09 in which
missing hydrogen bond were assigned subjected by energy
minimization (Figure 2-4).
Figure 3: Active sites in selected sirtuin proteins 1, 2,3,4,5,
and 6.
Figure 4: 3D structure of Sinapaldehyde.
The receptor network was groomed keeping ligand (Sinapaldehyde)
at the centre of framework with 20A edges bearing catalytic site.
Primarily docking simulation on the cocrystal was groomed on
prepared receptor for cross validating the binding ability with
subject to X-ray crystal structure binding mode. Moreover,
molecular docking method was implemented against
PDB ID employing Glide XP 5.8 [24-26]. and top analogs on
docking score as well as binding synergy with catalytic fragments
were allowed for induced fit docking and outcomes were compared
after Glide XP. The lowest energy suggested by Glide program was
noted as the most probable binding pose of top compound (Table
2).
Table 2: Physico-chemical properties of the ligand.
Ligand Molecular formula Molecular weight Monoisotropic mass
Heavy atom count Topological polar surface area
Sinapaldehyde C11H12O4 208.21 g/mol 208.073559 g/mol 15 55.8
Ų
http://dx.doi.org/10.32474/DDIPIJ.2020.03.000168
-
Citation: Sameer, Sudhakar Malla. Identification of Sirtuin Drug
Targets (Homosapiens) For Lung Cancer-Molecular Docking and ADME
Analysis. Drug Des Int Prop Int J 3(4) - 2020. DDIPIJ.MS.ID.000168.
DOI: 10.32474/DDIPIJ.2020.03.000168.
Volume 3 - Issue 4 Copyrights@ Sameer, et al.Drug Des Int Prop
Int J
405
Results and DiscussionActive binding sites of protein
molecule
In this study, FT site server was used to predict the active
sites of the targeted proteins (sirtuin 1, 2,3,4,5, and 6).
Ligand
Drug likeness analysis
Lipinski filter analysis was used to explain the rigidity of all
compounds to be considered for structure-based drug design (Table
3-5).
Table 3: Lipinski Filter Analysis.
Ligand Molecular formula Hydrogen bond donorHydrogen bond
acceptor cLogP Molar refractivity
Sinapaldehyde 208.21 g/mol 1 4 1.54 56.55
Table 4: Adamesar Analysis.
Properties Sinapaldehyde or
(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenal
Blood-brain barrier Yes (+)
GI absorption High
Permeability glycoprotein substrate No
Table 5: Molecular docking results against Sinapaldehyde
(ligand).
Receptors Score Glide energy (kcal/mol)
SIRT1 10280 -62.3
SIRT2 21764 -81.7
SIRT3 18508 -76.6
SIRT4 18258 -74.2
SIRT5 19800 -79.2
SIRT6 18808 -77.8
Molecular docking simulation
According to molecular docking simulation, results observed from
induced fit docking of compounds at the binding site of sirtuin
proteins showed better docking score than the already known
drugs for anticancer which predicts that the compounds have the
better binding affinity to the receptors. The molecular docking
result showed good binding affinity in all specific targeted
proteins (Figure 5,6).
Figure 5: Physico-chemical space of molecules with highest
probability of being utilized by the GI tract shown in white
region, whereas the yellow region shown the physic-chemical space
of molecules with highest probability to penetrate the brain.
http://dx.doi.org/10.32474/DDIPIJ.2020.03.000168
-
Citation: Sameer, Sudhakar Malla. Identification of Sirtuin Drug
Targets (Homosapiens) For Lung Cancer-Molecular Docking and ADME
Analysis. Drug Des Int Prop Int J 3(4) - 2020. DDIPIJ.MS.ID.000168.
DOI: 10.32474/DDIPIJ.2020.03.000168.
Volume 3 - Issue 4 Copyrights@ Sameer, et al.Drug Des Int Prop
Int J
406
Figure 6: Molecular docking simulation of sirtuin proteins (1,
2, 3, 4, 5, and 6) with ligand namely Sinapaldehyde. The docking
results showed that all selected compounds for docking exposed an
excellent binding affinity. SIRT2 showed highest glide energy
(-81.7) followed by SIRT5 (-79.2).
Conclusion In silico studies of the selected sirtuin proteins
(1,2,3,4,5, and 6)
showed the favorable result against ligand namely Sinapaldehyde.
The selected compounds exposed better outcomes in silico analysis
and characterization with good efficiency in aspects of docking
score and glide energy. According to ADME predictions,
Gastrointestinal absorption is very high and absence of
permeability glycoprotein substrate. Hence, it has assumed or
predicted that the compound (Sinapaldehyde) possibly serve as for
the treatment of lung cancer and might be in future be utilized in
in vivo studies to predict their effects on the abilities for the
cure of cancer.
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Identification of Sirtuin Drug Targets (Homosapiens) For Lung
Cancer-Molecular Docking and ADME
AnalAbstractKeywordsIntroductionMethodology Active binding site
Ligand formation Study of drug likeness of ligands Molecular
docking simulation
Results and Discussion Active binding sites of protein molecule
LigandMolecular docking simulation
ConclusionReferences