Identification of Alpha-glucosidase as a potential enzyme for the treatment of diabetes mellitus 2 by In-Silico approach
1.
INTRODUCTION
Diabetes mellitus is the disease of ineffectual control of
blood vessels of glucose. Type 2 diabetes mellitus (Type 2 DM) is a rapidly
increasing world health problem referred to as adult-onset diabetes. It is
called adult-onset as the patients are diagnosed later in life with this
disease. The symptoms appear late making the disease unidentifiable unless
around the age of 45. According to Raelic (2016) Type 2 DM is considered to be
the disease of middle or older aged people but with the increase of obesity and
unhealthy lifestyle Type 2 DM is increasingly being diagnosed at a younger age (Rahelić,
2016). On the onset of Type 2 DM
insulin feedback is diminished and this is called insulin resistance. About
3000 years ago an Egyptian manuscript first discussed insulin resistance. Type
2 DM is a multifactorial disease and develops from the presence of several
genetic, environmental, and behavioral factors. In other words, the interaction
of different factors contributes to the development of Type 2 DM. People having
Type 2 DM are more susceptible to different health complications including
heart disease and stroke. This study aims to identify alpha-glucosidase as a
potential enzyme for the treatment of diabetes mellitus type 2 disease.
2.
Key
Words
Type 2 Diabetes Mellitus,
Alpha-Glucosidase, Molecular Docking, Auto Dock Vina, In-Silico Drug
Identification, phytomedicines
3.
Research
Questions
1.
Is Alpha Glucosidase act as a potential enzyme for the treatment
of Diabetes mellitus?
2.
Is it possible to delay carbohydrate absorption from the small
intestine using Alpha-glucosidase inhibitors (AGIs)?
3. Is
there a potential in plant terpenoids to be used as inhibitors for pancreatic
amylase?
4. Is
it possible to reduce obesity and heart diseases in the world by treating
Diabetes Mellitus Type 2?
5. Can
Diabetes Mellitus Type 2 be treated by inhibiting alpha-glucosidase without disturbing
the bacterial flora of the human body?
4.
Objectives
1. To
virtually screen, a library of about 200 plant terpenoids against
alpha-amylase.
2. To
utilize the potential of alpha-glucosidase for the discovery of potent drugs
against diabetes mellitus type 2
3. To
indirectly treat obesity and heart diseases by treating diabetes mellitus type
2.
4. To
repurpose already existing plant terpenoids for the wellbeing of diabetes
mellitus type 2 patients.
5. Motivation of Research
According to research by Rahelic
(2016) with his colleagues examined
about a million people and submitted a systematic review and meta-analysis.
They concluded that the younger age diabetics are more to microvascular and
macrovascular complications and they are associated with an increased risk of mortality
(Rahelić, 2016).
According to World Health Organization,
T2DM was the 9th leading cause of death in 2019 (Diabetes,
n.d.). Globally in 2021, 462 million
individuals are suffering from T2DM and it counts for 6.28% of the world's
population. According to Ralph A. DeFronzo, the rate of Type 2 DM will be
increased to 591.9 million by 2023, which counts to a 55% increase in Type 2 DM
between 2013 to 2023 (DeFronzo et al., n.d.). There is
currently no cure for T2DM and its prevalence is increasing rapidly throughout
the world causing a high rate of mortality and morbidity particularly in
youngsters. Worldwide around 8.4% of deaths are caused by Type 2 DM and its
related microvascular or macrovascular complications, as stated by Rahelic in
2016 (Rahelić, 2016).
According to a report published by
Narayan and colleagues in 2020 (in an epidemiological study) that South Asians are more susceptible to
T2DM than other ethnic groups even at low BMI and they count
for almost 2 billion people on the Earth. Further Narayan and his colleagues
added that normal-weight south Asians are at more risk to get Type 2 DM as
compared to normal-weight people of other ethnic groups. (Narayan & Kanaya, 2020). Until now there is no definite
treatment for Type 2 DM or the metabolic dysfunction associated with it. Therefore,
there is an urgent need to unknot the cure for T2DM to upgrade the lifestyle of
T2DM patients.
6.
Research
Contribution
Several papers have been published that describe the effects
of Alpha Glucosidase inhibitors in type 2 diabetes, this research will
contribute to identifying more alpha-glucosidase inhibitors as an effective way
to control diabetes type 2. According to Dirir and his colleagues (2021), there
are just three approved inhibitors for alpha-glucosidase as a treatment for
Type 2 DM which include miglitol, acarbose, and voglibose. All of them have
their limitations, gastrointestinal side effects and none of them can be
considered as a promising treatment as Type 2 DM is related to several other
health complications and each patient should be prescribed the treatment
according to the severity of microvascular and macrovascular complications. (Dirir
et al., 2021a) There is a need to find new and potent
inhibitors for alpha-glucosidase and this research will contribute to the
fulfillment of this need. Academia will get advancement to the knowledge by
adding new knowledge through this research. Through this research pharmaceutical
industry can contribute to the well-being of society by finding a plant-derived
medicine for the treatment of the ninth most common disease in the world (Type
2 DM).
7.
Literature
Review
Diabetes mellitus can be treated by slowing starch
degradation in the intestine by using Alpha-glucosidase inhibitors. According
to Bashary et al (2019) type 2 diabetes is linked to diminished glucose
tolerance due to insulin resistance. Any injury in the islets of beta cells of the
pancreas can cause insulin deficiency that will greatly affect the consumption
of glucose by the liver, muscles, and adipose tissues which results in glucose
intolerance. Several other genetic, environmental and living conditions also
contribute to the development of insulin resistance. (Bashary et al., 2019).
7.1. Type 2 Diabetes Mellitus
According to Halim et al, the chronic Hyperglycemia
condition that results in a group of metabolic disorders is called diabetes and
this hyperglycemic condition is due to the deficiency in the levels of insulin.
In other words patients with type 2 diabetes mellitus reveal aberrant insulin
secretion and insulin action. Genetic, environmental, and some other factors
also contribute to T2DM. The main feature of type2 diabetes includes the lack
of demand for insulin which is obligatory for the prevention of ketoacidosis. . These impediments can generate substantial
influence on the organ system of the body. (Halim
et al., n.d.). According to Oguntibeju (2019), these
complications are divided into two groups namely vascular complications and
non-vascular complications. There are two types of vascular complications, one
is microvascular and the other one is macro complications. Neuropathy, nephropathy,
and retinopathy are microvascular complications whereas, macrovascular
complications include cerebrovascular disease (CVA), coronary artery
disease (CAD), coronary heart disease, and peripheral vascular
disease (PVD). Additionally, the researcher also suggested that the possibility
that an individual will develop cardiovascular diseases naturally increases
with the presence of diabetes (Halim
et al., n.d.) (Oguntibeju, 2019)
The popular non-insulin treatment for Type 2 DM is
modulation of pathophysiological abnormalities that relate to an increase in
glucose concentration in blood (hyperglycemia).
7.1.1
Beta
Cell Physiology in Type 2 DM:
According to Al-Mrabeh, the beta cells are the part of the pancreas
which is the largest gland of the body. Beta cells secrete insulin and along
with insulin pancreas participate in the production of glucagon through alpha
cells and somatostatin through gamma cells. Beta cells are stimulated through
hormonal productions and they can also be stimulated through non-hormonal
productions like zinc and ATP. In diabetic patients, the amount of beta cells
in the pancreas is found to be lowest than non-diabetics (Biomedicines
& 2021, n.d.)
7.1.2.
Insulin
Secretion:
In 2018 while talking about the mechanism
of insulin action Petersen and Shulman stated that beta-cells of the pancreas
sense the output from neurotransmitters, hormones, and different substrate
concentrations (e.g. Glucose and amino acids like arginine) and maintain the
plasma concentration of insulin accordingly. A non-diabetic person may only
need a 0.2 U of insulin for 2 hours in a daily working routine, while an obese
and insulin-resistant person will require 45 U of insulin for 2 hours in a
daily working routine. This difference in required plasma insulin concentration
depicts the importance of beta-cell secretion in a normal amount. Moreover, if insulin
secretion is impaired by beta-cell dysfunctioning, it may lead to hyperglycemia
which contributes to Type 2 diabetes (Petersen & Shulman, 2018).
7.1.3.
Insulin
Resistance:
According to the latest review
paper by Courtney and Olefsky (2021) Insulin resistance is caused by abnormal
secretion of insulin from beta-cells of the pancreas. Due to obesity, inactive
lifestyle and some genetic predispositions beta-cells experience stress and
exhibit a continuous decrease in their functioning and decline in the capacity
of beta-cells to secrete insulin, thus it caused them to secrete abnormal
concentrations of insulin (Courtney & Olefsky, 2021). Courtney and
Olefsky further added that mostly this decline in insulin secretion is observed
in the liver and muscle as the liver and muscle are mostly involved in the
absorption of carbohydrate through lots of channels in their cell membrane, but
the decline in insulin concentration can also occur in the gastrointestinal
tract, adipose tissue, kidney, and the brain. The metabolic consequences of
abnormal insulin concentration in different cells of the body lead to
hyperglycemia, hyperuricemia, and hypertension (Courtney & Olefsky, 2021).
7.1.4.
Mitochondrial Disfunction:
It is still the topic of debate that whether
mitochondrial dysfunction is the cause of insulin resistance or the result of
insulin resistance. According to Courtney and her colleague, impaired secretion
of adiponectin and an increase in the number of reactive oxygen species is
associated with mitochondrial dysfunction in adipose tissue and non-adipose
tissue respectively (Courtney & Olefsky, 2021).
7.2. Alpha-Glucosidase
The alpha-glucosidase enzyme is a hydrolase that converts starch
of dietary sources into simple sugars like glucose to fulfill the glucose
requirements of the body. Humans require this enzyme to use glucose from
complex carbohydrate sources. Dietary sources do not contain glucose in the
simple form and the complex form cannot be absorbed through the small
intestine. In the absence of deficiency
of these alpha-glucosidase in a normal person blood plasma can run out of glucose,
loss of ATP can occur and it can lead to serious complications and death. But, According
to Hedrington and Davis (2019) in their publication about the “Considerations
while using alpha-glucosidase inhibitors in the treatment of Type 2 DM”,
hyperglycemia (increase in blood glucose concentration more than normal) is the
most common complication in Type 2 DM and alpha-glucosidase is the source of
increase in blood glucose, inhibition of alpha-glucosidase can be the treatment
for the patients with Type 2 DM (Hedrington & Davis, 2019).
Moreover, according to Hedrington
and Davis (2019), alpha-glucosidase inhibitors are the class of non-invasive
drugs that can cause mild side effects including diarrhea. But, their side
effects are dose-dependent and short-lived. Thus, the side effects are cured
within a short time and can be managed by reducing the dose of the drug (Hedrington & Davis, 2019). Sometimes, the complications in
diabetes are caused by the poor dietary habits of the patient. Doctors always
recommend that diabetic patients avoid the consumption of exogenous sugar but
not following these guidelines of the doctor's patients often cannot restrict
themselves from sugar consumption leading to the consequences of hyperglycemia.
Alpha-glycosidase inhibitors could be the savior in such situations and these
drugs can be prescribed when the patient has intentionally or non-intentionally
consumed a large amount of drug. Before letting this glucose reach the blood
and cause type 2 DM complications the glucose can be made non-available to the
blood by restricting its absorption from the intestine.
According to Dirir et al (2021) until
now only three alpha-glycosidase inhibitors are being utilized in clinical
trials which are given as acarbose, miglitol, and voglibose (Dirir et al., 2021b) Their
structures are given in Fig 1.1. Therefore, it is required to find more inhibitors
for alpha-glycosidase with increased efficiency.
Fig
1.1
7.3. In-Silico Drug Designing
In-
Silico is a Computer-aided method for drug design playing an ever-increasing
role in drug discovery that is important in the cost-effective recognition of
promising drug candidates.
According to Chandrasekaran et al (2018) in-silico, drug
designing is extensively applied in drug discovery and designing. In this
process, recognition of the suitable drug target is the first and foremost task.
Recognition of such targets is necessary to expose a sufficient level of
‘confidence’ and to know their pharmaceutical application to the disease under inspection
(Chandrasekaran
et al., 2018)
According to Guan et al (2019) in silico drug designing is
the need of the time. One of the benefits of this technique is that it requires
less time, less financial resources, and is more effective. According to
various needs of the experiments and differentiating nature of compounds,
in-silico drug designing or computational drug designing is classified into two
groups, which are structural-based drug designing and ligand-based drug designing
(Guan et
al., 2019). Ligand-based drug design will be used
in this research.
7.4. Ligand-based approaches in drug
repurposing:
Drug repurposing is the advancing
field of drug designing in which the previously approved drugs are studied to
check if they have an affinity for other compounds (unintended targets) and if
they can be used to treat another disease. Drug repurposing is also named drug
repositioning. Thus by repurposing drugs scientists design new treatments from
the same drug and these newly designed drugs are not needed to be tested in
clinical trials as they have previously been approved and have gone through
clinical trials (sciences & 2013, n.d.).
According to Gaulton et al (2017), in
drug repurposing, the ligand-based approach is the method of repurposing a drug
by assuming that ligand with similar structure will have similar properties and
thus can be utilized in similar functions (Gaulton et al., n.d.). Databases like
drug bank, ChEMBL, and PubChem contains thousands of compounds that are from
various sources. Some of these compounds are approved as drugs, some are
reported for various biochemical activities. Researchers in the ligand-based
approach of drug repurposing take compounds to form these databases and use
them to check if they have interactive properties for any of their targets.
Accordingly, ligands are small
compounds that have been isolated in the laboratory by scientists and their
structures have been determined through various techniques like X-ray
crystallography, and after that their structures have been submitted in the in silico
databases. Thus, these structures make a library of compounds in the form of
databases. These databases are the
representation of the huge reservoir of different kinds of information like
their ADMET properties (Properties about the Absorption, Distribution,
Metabolism, Excretion, and Toxicity), binding affinity, and their different
structural aspects (Gaulton et al., n.d.). According to
Shameer et al (2017), the advances in in-silico drug repurposing have developed
databases that contain properties like bioactivity data and therapeutic
properties (Shameer et al., n.d.).
According to Gaulton et al (2017),
the databases (e.g. ChEMBL, drug bank, and PubChem) have 3D structures of the
compounds these compounds can be downloaded in different forms and they can be
prepared using different software tools as if they are being prepared in the
laboratory. After that, they are interacted using different online or offline
tools and their interactions can be seen with the target compound. Good
interactions in the in silico experiments are the evidence of their good
supposed interactions in vitro and in vivo (Gaulton et al., n.d.).
7.5. Molecular Docking
According
to Kitchen et al (2004) molecular docking is a tool for drug repositioning.
Several drug designing and drug repurposing approaches can be utilized by using
the tool of molecular docking. Whether it is a ligand-based drug designing
approach or any other approach the basic principle in molecular docking is the
same. Molecular docking tools predict whether two compounds can bind to each
other or not. The results are shown as binding affinity and binding energies. The
lower the binding energy, the better the drug can bind to the target. On the
other hand, the higher the binding affinity, the better the drug can bind to
the target (Kitchen
et al., n.d.).
Recently it was reported by Dakshanamurthy et al (2012)
molecular docking has become very successful in in-silico drug repurposing and
drug designing (Dakshanamurthy
et al., 2012). As discussed by Kitchen et al (2012)
in molecular docking for example if the ligand-based approach is applied)
different small compounds (ligands) have been taken from different databases
and they are prepared by using different tools after preparation these small
compounds are docked in docking software such as auto dock vina. Further stated
by Kitchen et al (2012)The interactions of the ligand and the target can be
seen by docking and by different algorithms several properties can be
predicted. The interactions and other properties predict whether a ligand can
be used as an inhibitor for a certain compound or not (Kitchen
et al., n.d.).
7.6. Auto Dock Vina
According to Muzio Auto dock, vina
is a molecular docking tool. That is used to check the interactions between any
two compounds. One of these compounds is the predicted drug which is chosen due
to several previous publications indicating the role of the compound in a
certain disease or the property of the compound that predict its affinity for a
second compound. While the second compound is a biochemical target that is
involved in the prognosis of a disease and its inhibition can cure a disease.
The biochemical target is a large compound mostly an enzyme while the ligand is
a small compound. The quality of interactions is determined by several inbuilt
algorithms in auto dock vina (Muzio et al., n.d.).
7.7. Phytomedicines:
Phytomedicines are plant-based
drugs that are extracted from the roots, shoots, leaves, bark, or any part of
the plant. They are plant secondary metabolites and have several different
functional groups that have the affinity for binding with the biochemical
target molecule in the body in physiological conditions. Till 2021, many plant-based
medicines have been approved by FDA and are being utilized for the treatment of
different diseases and disorders (Ben Hlel et al., 2021). According to
Wu and Charles (2020), these drugs are called botanical drugs and are named
Veregen (approved in 2006) and Fulyzaq (also named Mytesi) in 2012. Although it
is still a scientific challenge to describe their regulatory consistency (Wu et al., 2020).
Ben
Hlel in 2021 argued that For complicated metabolic disorders like diabetes and
obesity plant-based drugs can prove to be effective. Going through the history
of metabolic disorders, one can find that whenever conventional medicines have
no way out and no cure for the disorders, traditional medicines always have
shown their potential as stated by Ben Hlel (Ben Hlel et al., 2021).
8.
The Research Model
Figure
1.2
Figure
1.2: Research Model
In this research model, some simple but
expertized steps will be performed and different software will be utilized at
different steps. As indicated by the model the first step will be the Selection
of both the ligands and the target. The second step will be the preparation of
both the ligands and the target. In the third step both the prepared ligands
and the target will be interacted by using molecular docking software. Auto
dock vina will be used as molecular docking software in this research. In the
end, the results will be interpreted based on different values shown by the
autodock vina. These values will indicate the strength of the interaction of
the ligands and targets and thus predict the possibility of the binding of the
ligand and the target. Precisely speaking the ligands will be the terpenoids
extracted from the plant and the target molecule will be the alpha-glucosidase.
Furthermore, the molecular docking
strategy that will be used in this study is ligand-based drug designing and the
research analysis is quantitative.
9. The Hypothesis of
the Research Study
Plant terpenoids will prove to be the potential inhibitors
for the enzyme alpha-glucosidase contributing to the treatment of diabetes
mellitus type 2.
10. Research Gap
Till now there is no conclusive
treatment for Type 2 DM that can curatively reduce the metabolic dysfunction
and complications related to Type 2 DM. According to Aziz (2012), the most considerable
cause of the complications of Type 2 DM is hyperglycemia. Various approaches
have been utilized to treat the complications of Type 2 DM by treating
hyperglycemia, which is the increase in plasma or blood glucose concentration
more than normal. Further, Aziz stated that among these approaches and
treatments most famous ones are the use of injectable insulin for the treatment
of Type 1 DM and the use of drugs in combination with injectable insulin in the
case of Type 2 DM (M. A. Aziz, 2012). But,
Chatterjee and Davies (2015) in “Current management of Diabetes Mellitus and
future directions” added to this that rather than treatming Type 2 DM by
injecting insulin that could be harmful and can contribute to insulin
resistance and other physiological complications Type 2 DM can be treated by
using medications than will directly target the factors that are increasing the
glucose concentration in the plasma contributing to hyperglycemia. These
medications are termed as non-insulin medicines and are more useful for the healthy
life style of the diabetic patients (Chatterjee & Davies, 2015).
As investigated by Bhowmick and
Banu in their recent publication about the “Therapeutic targets of Type 2
Diabetes ” in 2017, a way to manage the glucose concentration in the plasma is
to suppress the absorption of glucose from the intestine so if it is being
ingested through the exogenous way it will not reach to the blood it can be
done by inhibiting the enzymes that are responsible for the absorption of
glucose from the intestine. Another way is to suppress gluconeogenesis
(synthesis of glucose from non-carbohydrate sources) from the liver. This
gluconeogenesis is called hepatic gluconeogenesis (Bhowmick et al., n.d.). Further added
by Bhowmick and Banu (2017) a third dominant way to maintain glucose
concentration in the plasma or blood is to decrease reabsorption of glucose
through kidneys. Glucose, when filtered through kidneys, is often taken back in
the blood from the kidneys this is called the reabsorption of glucose from the
kidneys. All of these three ways of treating hyperglycemia are termed
non-insulin medications and the most prominent non-insulin medications include
alpha-glucosidase inhibitors and sodium-glucose co-transporter 2 inhibitors (Bhowmick et al., n.d.).
Recently many researchers have proved the importance of
alpha-glucosidase as a target enzyme and many classes of compounds have been
docked and virtually screened against it. Hedrington and Devis in 2019 and
Dirir and his colleagues in 2021, argued that the inhibition of
Alpha-Glucosidase is explicitly involved in treating diabetes mellitus type 2.
Alpha-glucosidase should be studied at a higher level to evaluate and deploy
its capability for the treatment of one of the most frequent metabolic
disorders of the world; diabetes mellitus type 2 (Hedrington
& Davis, 2019) (Dirir
et al., 2021b). The most common anti-diabetic drugs
that work by inhibiting alpha-glucosidase and retarding carbohydrate digestion
include Acarbose- Precose or Glucobay (Hedrington
& Davis, 2019) (Dirir
et al., 2021b).
Further
Dirir (2021) added that various medicinal plant extracts have been studied for
suppressing alpha-glucosidase and they have shown surpassing outcomes than
acarbose but they interfere with gut flora and produce anti-nutritional effects.
After acquiring satisfying results, selected compounds were passed through
different phases of clinical trials before reaching the market. Previously
endorsed drugs should be screened against alpha-glucosidase to identify if any
of them can be repurposed as a potential inhibitor of alpha-glucosidase (Dirir
et al., 2021b).
11.
METHODOLOGY
11.1 Research Design
The research
design is ligand-based drug designing. Plant terpenoids are selected as ligands
as some terpenoids have shown good interactions with alpha-glucosidase. Based
on the ligand-based drug design approach the related compounds will suppose to
be showing good interactions with the alpha-glucosidase.
Furthermore, the
research model shown in figure 1.2 will be followed. The first step, the
selection of ligand and the target molecule has been performed. As discussed
earlier the plant terpenoids are selected as the ligands and alpha-glucosidase
enzyme is the target molecule. The second step will be performed now which is
the preparation of the active sites of both ligands and target molecules. Then
they will be docked in auto dock vina software.
11.2 Sampling Procedure
and Sample Size
Following the
in-silico sampling methods, the procedure of sampling will be the downloading
of required compounds from the relevant databases and their libraries will be
made. Almost, 200 plant terpenoids will be selected as ligands and collected in
the form of a virtual library.
11.3 Sampling Technique
The drug
repurposing technique is utilized in this study. In this sampling technique plant
terpenoids will be screened against a targeted enzyme to repurpose and
reposition their role in diabetes mellitus type 2 (T2DM).
11.4 Tools of Data
Collection
Following
databases will be used as the tools of data collection.
·
PubChem
·
Protein Data Bank
11.5 Data Collection
Procedure and Methods
For the
collection of the data, PubChem will be used as a protein database. PubChem has
thousands of small molecules reported by researchers and the 3D structures of
these small molecules are available that can be downloaded and collected in one
place. Plant terpenoids will be found from PubChem by searching their names one
by one and by downloading their SDF file one by one. If the SDF file of any compound
will not be available. Its structure can be manually drawn using drawing
software like the Chemdraw. Or the canonical smile or isomeric smiles of these
ligands can be pasted in this software.
Moreover, the 3D
structure of the alpha-glucosidase will be downloaded from the Protein Data
Bank in the PDB file formate.
11.6 Data Analysis
Methods and Software
All the collected data will be
analyzed by using the following two software.
·
Open Babble
·
Auto Dock Vina
Open Babble is a simple software that
can convert ligand files from one format to another format. Any input format
can be converted to any open babble supported output format. Open Babble will
be used to convert the PDB file downloaded from the Protein Data Bank into a
pdbqt file. The ligand files that will be downloaded in SDF format will also be
converted to pdbqt files by using Open Babble software. The pdbqt format is the
only format supported by auto dock vina.
Moreover, Auto dock vina will be used to
perform rapid screening of protein-ligand interactions. After the conversion of
enzyme in pdbqt formate by open babble software, the domains of the enzyme will
be selected in the form of a grid in Auto Dock vina. It is necessary to select
the grid box otherwise the docking will not be performed. A grid box will limit
the sites of interactions of the ligands to the targeted enzyme. If there will
be no limit in the interactions thousands of possibilities will be found by the
software and the processor of the computer will not be capable of performing
such a heavy command. Thus the shorter the grid box the easier the will be
docking process and lesser time will be required accordingly. Ligands will be
provided the grid area to confirm their position of attachment.
Preparation of the grid area will be a
crucial process and it will be the process that will provide the direction to
the research. The grid area will be prepared by selecting the active domains of
the enzyme. Active domains will be found by reviewing the literature. The
literature will be studied that accordingly. Active domains will be found by
finding the sites where the ligands were previously bounded when the enzyme
will be downloaded in PDB format. In case of the presence of more than one
domain, more than one grid boxes will be made and docking will be performed
more than one time and the results of all the grid boxes will be interpreted
separately. This process will make the research more precise and effective. The
topmost effective ligands will be selected based on the lowest binding energies
of the ligands.
11.7 Expected Results
As some terpenoids have shown good
binding with the alpha-glucosidase it is expected that by following the ligand-based
drug designing approach the terpenoids that will be used in this research will
show good binding as well. Although all of the ligands may not have an
effective docking score, it is expected that most of the ligands will be found
to be potent inhibitors of alpha-glucosidase.
11.8 Time Frame to
complete the Research Study
1. Data
collection will require about a month
2. Data
preparation will require a month as well
3. Docking
will take about a week
4. Manuscript
writing will take about one month
12.
Total Required Time:
As
it is the computational drug designing, it will require a lesser amount of time
as compared to the in vitro or in vivo approaches. With the prowess and
proficiency in all the tools mentioned in the research proposal, this whole
research will be completed within 4 months with the completion of the manuscript
as well.
13.
Proposed budget:
There will be no need to buy any
samples, particularly for this study. The research will be performed with the
help of a good quality laptop and no budget will be required.
14.
Required apparatus:
This study will require a laptop with a
good working processer. Furthermore, some software will be required as
described previously in the proposal. This software will include Docking
software like Auto Dock vina. Moreover, Open Babble will be required for
forming pdbqt files and Pymol will be required to view the interaction between
ligands. Also, Chemdraw software will be required to draw compounds that will
not be downloaded from the PubChem in the form of SDF files.
15. Discussion
Type 2 diabetes is the disability of the body to regulate
and use sugar (glucose) as a fuel which causes a large amount of sugar to
circulate in the bloodstream. This high sugar level eventually leads to other
disorders of the circulatory, immune, and defense systems. Furthermore, type 2
DM can cause various microvascular and macrovascular complications.
There are two main reasons for this poor regulation of body
sugar. One is that the pancreas does not release enough insulin and the other
is that the cells badly respond to insulin and take in less sugar due to which
more glucose circulates in the blood. To compensate for the bad eating habits
of the patients it is necessary to develop medicines that can stop the increase
in blood glucose concentrations even if a high glucose diet is taken by the
patient. It can be done by stopping the conversion of glucose from the dietary
complex carbohydrates and eventually inhibiting the absorption of the glucose through
the small intestine in the blood.
Alpha-glucosidase is a hydrolyzing enzyme that breaks down the
starch of the food in the form of glucose to make the carbohydrate available to
the blood. Thus, the food items comprising of complex carbohydrates are
metabolized by alpha-glucosidase in the pancreas and transformed into glucose.
This glucose is fatal for T2DM patients. Inhibiting alpha-glucosidase
diminishes the formation of glucose by hydrolysis thus exogenous glucose
becomes no longer available to damage the body.
Plant-based medicines have been proved to be multipurpose
and beneficial especially in the case of metabolic disorders like diabetes and
obesity. Phytomedicines are the traditional medicines that have long been used
by ancient people but the biochemistry behind them was unknown till the advancements
in the sciences. Nowadays various plant extracts are being tested to check
their affinities for different targets. Several plant-based medicines have been
approved by FDA as well as discussed in the proposal earlier.
Moreover, there are only three small molecules (Acarbose,
Miglitol, and Voglibose) are in clinical trials. Thus there is a need to test
more plant-based compounds again the alpha-glucosidase to find more effective
and potent inhibitors. For this purpose, various plant terpenoids are extracted
from different sources which is the main focus of this research. By analyzing
the binding affinities of these Ligands with the targeted enzyme many other
potent drugs can be identified which can play major role in the treatment of
type 2 diabetes mellitus.
16.
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