Biochemistry Sample Research Synopsis for Master & PhD Research
MOLECULAR DOCKING OF ALPHA-AMYLASE BY REPURPOSING FDA APPROVED DRUGS
1 Dr. Iqra Ahmad (Biochemistry) 2 Dr. Muhammad Naeem (Business
Administration)
Laureate Folks International
https://laureatefolks.blogspot.com
laureatefolks@gmail.com, WhatsApp: +923334446261
1
INTRODUCTION
Diabetes mellitus type 2 (T2DM) is non-insulin-dependent diabetes mellitus characterized by increased blood glucose concentration and it is one of the most prevalent metabolic disorders. Almost 1 in 10 people are suffering from T2DM and it is a cause of obesity as well. There are several studies for the treatment of T2DM and some of them have drawbacks. This study aims to find a potential inhibitor for alpha-amylase as it directly participates in the formation of glucose from food. FDA-approved drugs will be screened in this study against alpha-amylase for repurposing their potential. Furthermore, there will be no need to check their drug-likeness and ADMET properties as they have already been approved by following all required properties.
Key Words: Type 2 Diabetes Mellitus, Non-insulin-dependent diabetes, FDA approved drugs, Alpha-Amylase, Auto Dock Vina, Molecular Docking, In-silico Drug Designing.
1.1 Research Questions
1.
Is there a potential for
FDA-approved drugs to be used as inhibitors for pancreatic amylase?
2.
Is it possible to reduce obesity
and heart diseases in the world by treating Diabetes Mellitus Type 2?
3.
Can Diabetes Mellitus Type 2 be
treated by inhibiting alpha-amylase without disturbing bacterial flora of the
human body?
1.2 Objectives
1.
To virtually screen, a library of
about 200 FDA-approved drugs against alpha-amylase.
2.
To utilize the potential of
alpha-amylase 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 drugs
for the wellbeing of diabetes mellitus type 2 patients.
1.3 Motivation
of Research
According
to World Health Organization, T2DM was the 9th leading cause of
death in 2019 (Diabetes,
n.d.). Globally 462 million individuals
are suffering from T2DM and it counts for 6.28% of the world's population.
There is currently no cure for T2DM and its prevalence is increasing rapidly
throughout the world causing a high rate of mortality and morbidity.
South
Asians are more prone to T2DM than other ethnic groups even at low BMI. They
include almost 2 billion people on the Earth according to a report published by
Narayan and colleagues in 2020 (Narayan & Kanaya, 2020). Insulin is
used as a therapy for Type 1 diabetes mellitus but administration of insulin is
not enough to treat T2DM as cells do not respond to insulin. There is an urgent
need to unravel the cure for T2DM to improve the lifestyle of T2DM patients.
Robust measurements and advanced modeling methods are required to be utilized
1.4 Research
Contribution
There
are several kinds of research to find alpha-amylase inhibitors, this research
will contribute to finding some more potent inhibitors that can be confidently
used for humans. Academia will get an advantage by discovering the potential of
FDA-approved drugs in repurposing their role in pancreatic enzymes. There will
be opened a new area of research if the potency of the used drugs in this study
exceeds previously utilized drugs in T2DM. There is a high chance that
industries will need to manufacture concluded drugs as a treatment of T2DM.
2
LITERATURE
REVIEW
Diabetes
mellitus can be treated by using FDA-approved drugs as inhibitors of
carbohydrate hydrolyzing enzyme alpha-amylase. According to McIntyre et al
(2019) Diabetes mellitus is a common non-infective disease characterized by
increased blood glucose levels. Diabetes mellitus has two types Type 1 diabetes
mellitus occurs due to decreased capacity of the pancreas to secrete insulin.
Whereas type 2 Diabetes mellitus occurs due to resistance to insulin by cells
and several other metabolic factors. Almost 90 to 95% of diabetics have type 2
diabetes (McIntyre et al., 2019).
2.1
Type
2 Diabetes Mellitus:
Type
2 Diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders
closely relevant to the pandemic of obesity. There is an impaired secretion of
insulin in diabetics which contributes to hyperglycemia. Not only insulin
secretion is below the required level, but also T2DM is characterized by
resistance to insulin. This insulin resistance is commonly called Insulin
resistance metabolic syndrome. Both impaired insulin secretion and insulin
resistance are core defects in T2DM but according to Bashary et al (2019),
there are other defects as well which contribute to non-regulation in glucose
metabolism (Oguntibeju, 2019) (Bashary et al., 2019). Moreover,
Narayan and colleagues (2020) reported that poor beta-cell function and lean
muscle mass contribute to impaired insulin secretion. Also, it was added that
fat deposition in the liver and muscle lead to impaired insulin functioning (Narayan & Kanaya, 2020).
According
to Oguntibeju (2019), T2DM can cause microvascular and macrovascular
complications. Microvascular complications include those complications which
affect small blood vessels. These examples include nephropathy, neuropathy, and
retinopathy. Macrovascular complications include the complications of arteries.
These examples include cardiovascular diseases and cerebrovascular diseases.
Cardiovascular diseases are the most common cause of death in patients with
T2DM. Moreover, peripheral artery diseases are also included in macrovascular
complications of T2DM. Both micro and macrovascular complications can occur in
non-diabetic patients as well. But hyperglycemia makes diabetics more prone to
these complications. Mostly heart attack is related to diabetes as diabetics
have more chance of having complications in their cardiovascular system (Oguntibeju, 2019).
2.2
Alpha-amylase:
Alpha-amylase
is present in the pancreas, hydrolyses alpha 1,4 glycosidic bonds, and
participates in the conversion of starch (amyloses and amylopectins), glycogen,
and maltodextrins to glucose. Considering the results reported by Oguntibeju et
all, it can be said that, all complications in T2DM occur due to an increase in
blood glucose concentration (Oguntibeju, 2019). Normalizing
blood glucose will treat the disease. Bashary in 2019 highlighted that a way to
normalize blood glucose concentration is to stop the formation of glucose from
the food. Thus inhibiting alpha-amylase will stop the formation of excess
glucose and lead to the normal blood glucose level (Bashary et al., 2019).
Inhibition
of alpha-amylase is one of the prime therapeutic strategies for the treatment
of T2DM. In 2018 it was published by the journal of drug delivery and
therapeutics in a study conducted by Pramod
Mourya that plant
extracts of alternanthera pungens Kunth showed inhibition
of alpha-amylase and alpha-glucosidase (In-Vitro
Studies on Inhibition of Alpha-Amylase and Alpha Glucosidase by Plant Extracts
of Alternanthera pungens Kunth | Journal of Drug Delivery and Therapeutics,
n.d.). Rocha et al (2019) used a panel
of chalcones with variable substitution patterns. At the conclusion of that
study, it was reported that the panel of chalcones with methoxy, hydroxyl,
fluoro, and Bromo substitutions show greater affinity towards alpha-amylase and
alpha-glucosidase (Rocha et al., 2019).
In another study conducted in 2019 by Raghu et al fucoidan
extracted from Turbinaria conoides showed favorable inhibitory properties for
alpha-amylase both in vitro and in silico. Inhibition of
alpha-amylase was reported as dose-dependent according to that study (Raghu
et al., n.d.). In the same year (2019) by Bashary and Khatik,
1, 3
diaryl-3-(arylamino) propane-1-one derivatives were designed,
synthesized, and reported as the antioxidants and the potential alpha-amylase
inhibitors. That method was in-silico and Auto Dock Vina was applied as the
tool for molecular modeling (Bashary & Khatik, 2019)
Moreover, Khadayat et al (2020) used the Microtiter
plate approach
for the evaluation of extracts of thirty-two Nepalese medicinal plants against
alpha-amylase. Their study concluded Nepalese medicinal plants might contain
certain ingredients that show inhibitory activity against alpha-amylase. They
suggested that the potential of medicinal plants should further be explored for
the treatment of T2DM (Khadayat et al., n.d.).
2.3
FDA
approved Drugs:
Food
and Drug Administration (FDA) approved drugs are those which have been tested
on their possible benefits and risks and their benefits are more than the risk.
These drugs are considered to be safe to use within the prescribed amount and
have passed through all stages of clinical trials. According to Kandeel et al,
FDA-approved drug repurposing means that the drugs will be tested against some
compounds and will be tested if they can be useful in some other impaired
physiological condition. Many a time the approved drugs are used for another
purpose thus reducing the need to pass through clinical trials and directly
reaching the market for the new treatment (Kandeel et al., n.d.).
Guan
et al reported in 2019 in his paper “ADMET score is a comprehensive scoring
function of evaluation of chemical drug-likeliness” that one of the properties
that should be qualified by a good drug is ADMET properties which include
Absorption, Distribution, Metabolism, Excretion, and, Toxicity (Guan et al., 2019). Checking these
properties is termed as a computer-aided prediction of pharmacokinetics. A drug
must qualify all of the screenings otherwise it could cause more harm than
good. Absorption means how much drug will be absorbed by the small intestine
and Distribution means how much an amount of the drug can reach the targeted
sites. In this study the targeted site is the pancreas hence the drug is not
needed to be absorbed thus a small quantity can be proved to be very
beneficial. Metabolism means its conversion into different metabolites. The
excretion of a drug is studied to check for how much time a drug can stay in
the body and according to this, it is prescribed either once or twice a day.
Toxicity is the amount of dose that can be harmful (Chandrasekaran et al., 2018) (Guan et al., 2019).
2.4
In-silico
Drug Designing:
In-silico
drug repurposing is regarded as an innovative and modern method to achieve reliable
drug design. According to Surabhi and Singh (2018), conventional methods of
drug designs take years to synthesize and react to different chemicals in the
laboratory. Moreover, a great number of resources are utilized and a huge
amount of money is wasted in extracting, storing, transporting, synthesizing,
and analyzing chemicals in vivo or in vitro. In silico drug, designing is the
need of the era and it takes less time, less money and it is efficient.
According to different needs of the experiments and distinguishing nature of
compounds, in-silico drug designing or computational drug designing is divided
into structural-based drug design and ligand-based drug design (Surabhi & Singh, 2018).
This will be the
ligand-based drug designing and molecular docking approach will be utilized as
a tool in it. Furthermore, this will be the quantitative research analysis.
2.5
Molecular
Docking:
According
to Pinzi and Rastelli (2019), molecular docking is a key tool used in in-silico
or computational data analysis where various ligands and proteins interact as
if they have been mixed in a test tube. It involves the identification of
therapeutic drug targets and their inhibitors. Virtual screening by molecular
docking predicts favorable protein interactions. (Pinzi & Rastelli, 2019) It is a
comparatively easy and less time-consuming method if one has the expertise.
Nowadays, it is a trend to use molecular docking techniques for finding the
compounds which have good binding affinities for the targeted enzyme or any targeted
protein (Morris & Lim-Wilby, 2008).
In
most cases, some additional steps are performed like checking drug-likeness on
Drulito and ADMET properties on Swissadme. FDA-approved drugs are not needed to
be tested on ADMET properties.
2.6
Auto Dock Vina:
The
auto dock is a graphic tool to assist molecular docking. It is different from
the auto dock in that later docking with multiple ligands can not be performed.
Although auto dock itself uses Perl software to perform multiplicand molecular
docking. Auto dock vina is the advanced version of the auto dock. It is used
for drug discovery by interacting with proteins and showing their binding
energies. Auto dock vina will be utilized in this research.
Auto
dock alone cannot perform molecular docking. Proteins and ligands are needed to
be prepared before being opened in the vina interface. Auto dock vina uses
additional software for the preparation and conversion of virtual library
compounds. Also, it uses different software for the visualization of
ligand-protein interactions. All of this software will be discussed in this
proposal.
Through all these
studies it is confirmed that there is a dominant role of alpha-amylase in the
treatment of diabetes mellitus type 2 and scientists have been utilizing the
hydrolyzing potential of alpha-amylase to reduce exogenous glucose reaching in
the bloodstreams. Different plants have been utilized for the inhibition of
alpha-amylase and in silico invitro and in vivo studies have been conducted
recently to find a potential inhibitor for alpha-amylase. FDA-approved drugs
have not been screened for alpha-amylase till now.
3
The
Research Model
Figure
1.1
In this research model, some simple steps will be needed with the expertise in some docking software that will be discussed later in the proposal. This will be the ligand-based drug designing and molecular docking approach will be utilized as a tool in it. Furthermore, this will be the quantitative research analysis. The methodology will be divided into three stages as depicted in figure 1.1
1.
Selection
2.
Preparation
3.
Docking
In selection
ligands and the targeted enzyme will be selected. In this study, the ligands
are FDA-approved drugs and the target enzyme is alpha-amylase or pancreatic
amylase. Then both of them will be prepared to be used for docking. All the
ligands will be converted to pdbqt files as this file is required to be
prepared to input data in Auto Dock Vina for molecular docking. The targeted
enzyme will be prepared by removing extra side chains and all bounded ligands.
Also, the grid will be selected to allow the dimensions for interactions. In
the end, the enzyme will also be converted to pdbqt file and preceded to
docking. Docking results will be visualized in the form of scores.
4
The
hypothesis of the Research Study
·
FDA-approved drugs will be proved to be
the potential inhibitors for alpha-amylase hereby providing treatment for Type
2 Diabetes Mellitus.
5
THE RESEARCH GAP
Inhibition
of Alpha-amylase is directly involved in treating diabetes mellitus type 2 (Bashary et al., 2019). Alpha-amylase
should be studied at a higher level to estimate and utilize its potential for
the treatment of one of the most prevalent metabolic disorders of the world;
diabetes mellitus type 2. Recently many researchers have confirmed the
importance of alpha-amylase as a target enzyme and many classes of compounds
have been docked and virtually screened against it. The most common
anti-diabetic drugs that work by inhibiting alpha-amylase and slowing
carbohydrate digestion include acarbose (Pathak S and
Narula N. Optimization of PH for the... - Google Scholar, n.d.).
Many
medicinal plant extracts have been studied for inhibiting alpha-amylase and
they have shown better results than acarbose but they interfere with gut flora
and produce anti-nutritional effects. Also, Carbonaro et al reported that
giving more than the required dose will cause a reduced glycemic response which
can cause various health complications (Carbonaro et al., 2001; Heo et al., n.d.).
On
satisfactory results selected compounds to pass through different phases of
clinical trials before reaching the market. Previously approved drugs should be
screened against alpha-amylase to discover if any of them can be repurposed as
a potential inhibitor of alpha-amylase.
6
METHODOLOGY
6.1
Research
Design
The
research will be performed following the steps in figure 1.1. Previously
discussed steps; target and ligand selection, target and ligand preparation,
and the interaction of target and ligand by docking.
6.2
Sampling
Procedure and Sample Size
As
it is a computational study, in-silico sampling will be performed and the
libraries of the ligands will be made. 200 FDA-approved drugs will be selected
as ligands and collected in the form of a virtual library.
6.3
Sampling
Technique
The drug repurposing technique is utilized in this study. In this sampling technique, FDA approved drugs are screened
against a targeted enzyme to repurpose their role in diabetes mellitus type 2 (T2DM).
6.4
Tools
of Data Collection
Following
databases will be used as the tools of data collection.
·
Drug Bank
·
Protein Data Bank
6.5
Data
Collection Procedure and Methods
Protein
Databases will be used for the collection of ligands. FDA-approved drugs will
be collected from Drug Bank; a database that has all the FDA-approved drugs
available in one place. The 3D structure of each drug will be downloaded in the
form of a PDB file. Moreover, the 3D structure of the enzyme will be downloaded
from Protein Data Bank in PDB format.
6.6
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 will be used to convert the PDB file into a pdbqt file and 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 highlighted 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. Ligands will be provided the grid area to confirm their position of
attachment.
The grid area will be prepared by selecting the active domains of the enzyme. Active
domains will be found by finding the sites where the ligands were previously
bounded when the enzyme will be downloaded in pdb format. If there will be more
than one domain and the grid will be covering most of the area of the enzyme then
more than one grid will be selected and docking will be performed more than one
time in Auto Dock Vina.
The lowest binding energies will be
shortlisted and the topmost effective ligands will be selected.
6.7
Expected Results
Docking
scores or scoring function will expectedly be lower than the standard that will
indicate the usefulness of the molecular docking analysis. Lower the docking
score more will be the affinity of the ligand to bind to the target. All the
drugs may not show good potential for inhibiting the targeted enzyme but some
of them will expectedly be the potential inhibitors of the targeted enzyme.
6.8
Time
Frame to complete the Research Study
1. Data
collection will require about 5 days
2. Data
preparation will require 5 days as well
3. Docking
will take 2 days
4. Manuscript
writing will take about one month
7
Required
Time:
Computerized
drug design has become a choice due to the least amount of time utilized in
this procedure. With the expertise in library designing and in-silico docking
methods this will take about 2 weeks in doing experiments and one month in
finalizing the manuscript.
8
Proposed
budget:
No
budget will be required as there is no need to buy any samples, particularly
for this study.
9
Required
apparatus:
This
study will require a laptop with a good working processer. Docking software
like Auto Dock vina will be required 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 cannot
be downloaded from the Drug Bank.
10
DISCUSSION
Diabetes
mellitus Type 2 disease is a chronic illness that is untreatable till now and
can cause mortality. In this disease, there is an increased concentration of
glucose in the blood that is unable to reach the cells. It is called
hyperglycemia. Hyperglycemia can cause various other illnesses including obesity
and heart diseases. Complex carbohydrate-containing food items are hydrolyzed
by alpha-amylase in the pancreas and converted to glucose. This glucose is
dangerous for T2DM patients. Inhibiting alpha-amylase reduces the formation of
glucose by hydrolysis thus exogenous glucose becomes no longer to be damaging
for the body. For inhibition of alpha-amylase FDA approved drugs will be
virtually screened in this study using the auto dock vina.
The
inhibition of carbohydrate hydrolyzing enzyme, alpha-amylase by FDA-approved
drugs will be the main purpose of this research. By strong binding affinities
of FDA-approved drugs against the targeted enzyme (alpha-amylase) one or more
potent drugs may be identified through this research. Reducing blood glucose by
inhibiting alpha-amylase will treat hyperglycemia and thereby it will be proved
to be a cure for Diabetes Mellitus type 2.
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