|Natural anticancer molecule; Bioinformatics; PASS
|Cancer is disorder of cells growth. It starts when a normal cell
begins to grow in an uncontrolled and invasive way. Cancer is thought
to be caused through the interaction between genetic susceptibility and
environmental toxins . There are several ways which are applied for
cancer treatment, for instance: Surgery, Chemo-therapy, Immunotherapy
(monoclonal antibody), Radiotherapy and Gene-therapy.
|Chemotherapy is a kind of cancer treatment; it acts by destroying
cells which are dividing rapidly. It means that it also has an effect on
normal cells, such as: bone marrow, digestive tract, and hair follicles.
Therefore, it results in side effects on patients who are exposed to
chemotherapy. Most of the chemotherapeutic drugs target mitosis cell
division in order to inhibit the hyperproliferation state of tumor cells
and subsequently induce apoptosis. The majority of chemotherapeutic
drugs can be clustered in alkylating- agents, antimetabolites,
anthracyclines, plants alkaloids, topoisomerase inhibitors and other
antitumor agents. The anticancer drugs can be subdivided in three main
groups based on their mechanisms of action: (i) drugs that interfere
with DNA synthesis, (ii) drugs that induce DNA damages, (iii) drugs
that inhibit function of the mitotic spindle . Plants are important
source of anticancer agents and plant-derived compounds have played
crucial role in development of several useful clinical anti-cancer drugs.
|Bioinformatics is the mathematical, statistical and computing
method that aims to solve biological problems. Bioinformatics can
be applied in the field of medical sciences to consider the molecular
pathways of diseases . By developing sophisticated bioinformatics
software’s such as PASS (Prediction of activity spectra for substances);
it is now possible to predict some targets of anticancer molecules on the
basis of structural formula of a substance accurately. This study focused
on some natural anticancer molecules, including: Docetaxel, 7-xylosyl-
10-deacetyl paclitaxel, Pseudobaptigenin , Kabophenol A, Carasinol B, 7β-hydroxysitosterol, Dehydrocostuslactone, and Artemether. By
applying PASS software, we found targets of these natural molecules
and classified them based on their targets in cancer pathway. We believe
that it can be as an efficient approach for recognizing new mechanisms
of anticancer compounds.
|Materials and Methods
|A practical database is the main step in bioinformatics projects.
Collection of data from Pub med database was accomplished with
general keyword “anticancer”. Most data were gathered from 2010
papers; therefore, known anticancer molecules and some information
relevant to their targets in apoptotic pathway were extracted from these
papers. In this case, molecules were classified based on their origins. As
a result, there were 7 groups of anticancer molecule such as Drug Bank,
plants, fruits, microorganisms, semi-synthetic, synthetic and finally
ungrouped anticancer agents .
|Structural formulas of these molecules were investigated from
Chemspider, Pubcheme and Wikipedia, respectively in order to
discover orginal molecular structure of all compounds. Then, their
skeletal structures were drawn by Chemschetch, Chemaxon and version
5.4 software. ChemAxon is a leader in providing Java based chemical
software development platform for biotechnology and pharmaceutical
industries and is applied to reach 3D structure of molecules within
MDL SD file, Protein Data Bank (PDB), Tripos MOL2 formats (Figure 1).
|PASS (Prediction of Activity Spectra for Substance) is a simple
computational tool that can predict more than 1500 pharmacological
effects, molecular mechanisms of action and toxicities based on
structural descriptors of compounds with over 80% accuracy. It also has capability to predict many types of activity for a new substance.
PASS normally utilizes input data with molecular structure Protein
Data Bank (PDB), Tripos MOL2, MDL MOL and SD file formats
then represent the structural information about molecules under
study. PASS prediction can be interpreted by Pa and Pi values. Pa
and Pi values are as measures that determine activity and inactivity of
compounds. Pa –the probabilities of being active and close to 1.000, Pi
–the probabilities of being inactive close to 0.000; therefore, the Pa and
Pi values are vary from 0.000 to 1.000 and in general Pa+Pi<1.
|PASS software works successfully on a PC running Vista, windows
7 and XP. In this study PASS version 1.917 was applied (Figure 2) and
molecules with Pa more than 0.6 have been selected and categorized
based on their targets in cancer pathway.
|MNA (Multilevel Neighborhoods of Atom) descriptors are one the
sections in PASS software that are utilized for assessing of chemical
similarity based on 2D description of molecules and appropriate for
use in QSAR (Figure 3). According to (Robustness provoke) MNA
descriptor doesn’t specify the bond type and comprises hydrogen
according to a valence and partial charge of atoms; thus, it is based on
|Nearly 242 molecular structures were collected from PubChem, Chemspider database and Google search, these compounds were
evaluated by PASS software in order to screen compounds with high
anticancer activity and specify their targets during cancer pathway.
Among these natural molecules, approximately 9 agents revealed
anticancer activity with Pa more than 0.6 and they targeted specific
proteins throughout cancer pathway. As it can be seen from Table 1,
Docetaxel and 7-xylosyl-10-deacetyl paclitaxel are as Microtubule
formation inhibitors, β-tubulin antagonists, antimitotic agents because
they showed Pa>0.6. Thus, according to their high Pa scores these
molecules are as promising anticancer agents. It can be seen form Table 2 that mentioned agents target PTK, Topisomerase I, MYC, DNA and
protein efficiently and Artemether with Pa 0.8 are categorized as the
most strong agent compare to other 6 molecules .
|PASS software also has capability to estimate drug likeness of
under study agents. Drug-likeness referred to specific score estimated
from the molecular structure and indicated that specific molecule have
some proportional properties which can be active biologically or might
show therapeutic potential. Consequently, all 9 agents exhibited druglikeness
more than 0.9 and it means that they can be applied as drug.
|In this paper, a mathematical approach is discussed to evaluate
anticancer activity of molecules based on Pa activity. PASS (Predication
of Activity Spectra for Substances) software capable of anticipating
more than 1500 pharmacological effect that can be efficiently applied
to find new targets for some ligands to reveal new biological activity of
various substances as natural molecules have less side effects compared
to synthetic ones, we tried to discover new natural anticancer drugs
which target specific cancer targets efficiently and develop the spectrum
of efficient anticancer of molecules.
|Microtubules are key components of cytoskeleton, and are formed
from tubulin molecules. They have crucial role in development and
maintenance of cell shape, in transport of vesicles, mitochondria and
other components throughout cells, in cell movements, in cell signaling
as well as in cell division and mitosis . Microtubules are the target of
variety of specific antimitotic drugs. Antimitotic drug exerts its effect
by causing disorganized stabilization of microtubules in area away
from the centriole or causing destabilization of mitotic spindle which is interfering with mitosis . Docetaxel is semisynthetic analogue of
Paclitaxel and they bind to microtubules with high affinity in order to
stabilize microtubules and prevent from depolymerization. 7-xylosyl-
10-deacetyl paclitaxel is isolated from Taxus Chinensis,which exhibits
higher water solubility than Paclitaxel  demonstrated that 7-xylosyl-
10-deacetyl paclitaxel induced mitotic cell cycle arrest and apoptosis.
|It can be seen from Table 1, both molecules have microtubule
formation inhibitory, Docetaxel exhibited higher Pa score (0.986)
compared to 7-xylosyl-10-deacetyl paclitaxel (0.757) and it means
that Docetaxel can prevent from forming microtubules with more
strength. In addition, they are as β-tubulin antagonists too and there
isn’t apparent difference among their PASS thresholds, therefore,
they reveal this property with the same strength. Moreover, Docetaxel
and 7-xylosyl-10-deacetyl paclitaxel have strong antimitotic activity
and their scores are 0.992 and 0.868 respectively. As a result, both
molecules are promising anticancer agents which act through binding
to microtubules and tubulins. According to their drug-likeness score,
they can behave as an efficient drug.
|Protein Kinases are vital components of signal transduction
pathways. They act through responding to the extracellular environment
for regulating both cell growth and modification. Protein tyrosine
kinases have enormous roles in cancer molecular pathogenesis, and
they are as potential target for anticancer drugs currently . There are
two classes of protein tyrosine kinase inhibitors. One is bound to the
ATP binding site and the other is bound to the substrate binding site
of the enzyme. For instance, Pseudobaptigenin is an isoflavone which
can be isolated from Trifolium pretense  revealed that this agent has
an antiproliferative effects, but no reference has been indicated to the
principle target of Pseudobaptigenin in cancer pathway. Fortunately
our results revealed that Pseudobaptigenin with 0.702 PASS score has
high Protein Tyrosine Kinase inhibitor activity.
|DNA topoisomerases are a class of enzymes involved in
the regulation of DNA super coiling during replication. Type I
topoisomerases cut one strand of double-strand DNA, relax the
strand and reanneal the strand . Kabophenol Aand Carasinol B are stilbene tetramers, which can be isolated from Caragana chamague
and Caragana sinic. It is demonstrated that Kabophenol Ahas effect on
MCF-7 cells. While previous references didn’t mention to main target
of Carasinol B and Kabophenol Ain cancer pathway, we found that
these two molecules, which have 0.669 and 0.652 score chronologically,
have potent effects on Topoisomerase I. Therefore, they have anticancer
property and exert their anticancer effects by inhibiting Top I enzyme.
|Myc is a very strong Proto-oncogene which is expressed at elevated
levels in different types of tumors. Myc is as a suitable target for
development of novel cancer therapies and by designing drugs which
inhibit tumor cell proliferation and/or increase apoptosis; we can
extend the spectrum of anticancer agents. 7β-hydroxysitosterol, is a
type of sterol, is extracted from Sellaginella Tamarriscina  revealed
that this molecule exhibited potent cytotoxicity. Our results suggested
that 7β-hydroxysitosterol by exhibiting 0.657 PASS threshold has strong
Myc inhibitor activity.
|Aromatase is an enzyme, which is a member of cytochrome
p450 superfamily, it is located in the endoplasmic reticulum of the
cell. The aromatase enzyme can be found in many tissues including
gonads, brain as well as in tissue of endometriosis, uterine fibroids,
breast cancer and endometrial cancer. Therefore, aromatase is as a
critical target for cancers treatment. Aromatase inhibitors are class of
drugs used in treatment of cancers; these agents block the synthesis
of Estrogen in order to reduce the level of Estrogen. Consequently,
the rate of cancer growth will be slowed. Dehydrocostuslactone is a
sesquiterpene lactone extracted from Saussurea lappa and Aucklandia
lappa. Dehydrocostuslactone induces cell cycle arrest at G2/M, causes
cell cycle arrest via CDK1 down-regulation. According to our PASS
results, this natural agent by exhibiting Pa 0.656 is an aromatase
inhibitor agent and its high Drug-likeness score (0.995) related to the
fact that it might possess functional groups or has physical properties
which are consistent with most of known drugs .
|DNA synthesis (DNA replication) refers to the process of copying
each DNA strand into a new complementary strand. DNA replication
inhibitors are commonly used as anticancer agents. Artemether is
a methyl ether derivative of Artenisinin is isolated from the leaves
of Artemisia annua  demonstrated that the natural agent arrests
cell cycle at G2. Fortunately this agent exhibited the highest Pa score
(0.801) in compare to other agents and it means that Artemether is as
a strong DNA synthesis inhibitor and can be as promising anticancer
|Protein synthesis is the process in which cells build proteins. A
previous study showed that deregulation of protein synthesis is a major
contributor in cancer initiation and metastatic progression. Acemannan
is a D-isomer mucopolysaccharid in Aleo vera leaves . This
compound displayed chromatin condensation, DNA fragmentation
and laddering characteristic of apoptosis. It is notice worthy that
Acemannan with 0.613 Pass threshold has protein synthesis inhibitor
properties and it acts by inhibiting protein synthesis.
|On basis of our study, it is mentioned molecules have strong
anticancer characteristic and among all of them Docetaxel, 7-xylosyl-
10-deacetyl paclitaxel and Artemether by exhibiting the highest PASS
score are the most potent agents in our research. In addition, we found fundamental target of Pseudobaptigenin kobophenol A and Carasinol B throughout cancer pathway in order to provide new insight of
subsequent research into these agents because in vitro and in vivo
experiments of these finding haven’t been applied until now. It is
supposed that by applying these types of experiment new properties of
these molecules will be appeared.
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