Biosci. Biotech. Res. Comm. 11(2): 277-284 (2018)
Docking of GSK-3 with novel inhibitors, a target
protein involved in Alzheimer’s disease
Akanksha Joshi, Archit Sharma and Rajesh Kumar*
Department of Biotechnology, University Institute of Engineering and Technology. Kurukshetra University,
Kurukshetra, Haryana, India
Alzheimer’s disease (AD) is a chronic, advancing malady associated with loss of memory or cognition. It is the noted
causes of lethality worldwide, there are no such drugs which can cure AD till date and are ineffective in the later
stages. Such known drugs only ease the symptoms but do not prevent the onset or progression of the AD. Alzhei-
mer’s is caused by the aggregation of the hyperphosphorylated tau which is one of the common characteristics of the
neurodegenerative disorder. There are a number of kinases which hosts the excessive phosphorylation of tau protein.
One of the kinase extensively targeted in the AD is GSK-3 (Glycogen Synthase Kinase-3). As indicated by many
studies that by applying appropriate docking methods, a number of phyto compounds have shown enhanced target
selectivity than the conventional Alzheimer’s drugs. This review summarizes the known drug targets in the AD, their
conventional inhibitors and also the comparison between the current and future AD therapy based on their binding
af nities. As a result, large libraries of compounds with inhibitory effect can be screened. It was also studied that
Withanolide-A has the potential to be the future drug for Alzheimer’s disease.
*Corresponding Author:
Received 16
March, 2018
Accepted after revision 18
June, 2018
BBRC Print ISSN: 0974-6455
Online ISSN: 2321-4007 CODEN: USA BBRCBA
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© A Society of Science and Nature Publication, Bhopal India
2018. All rights reserved.
Online Contents Available at: http//
DOI: 10.21786/bbrc/11.1/13
Alzheimer’s is a type of dementia associated with mem-
ory loss and other intellective abilities, severe enough to
intrude with regular routine. Alzheimer’s disease report
for 60 to 80 percent of dementia and the present Alz-
heimer’s disease therapies impaired from in pro cient
effects on its symptoms such as perception notably in
the subsequent stages of the disease (http://www.alz.
org). According to the report prepared by Alzheimer’s
and related disorders society of India in 2010, there are
3.7 million Indians suffering with dementia while the
Akanksha Joshi, Archit Sharma and Rajesh Kumar
numbers are anticipated to bifold by 2030.
The num-
ber of factors is thought to increase the progression of
this disease, some of which are; increasing age, fam-
ily history, previous severe head injuries etc. Over the
past decade, much of the research on Alzheimer disease
(AD) has focused on radical-effected oxidative stress
and its importance in disease pathogenesis. Oxidative
stress increases amyloid beta deposits in the brain which
results in the synthesis of neurotoxic aggregates. The
net effect of oxygen radicals is damaging as it may
lead to neuronal cell death and contribute to AD (Smith
et al. 1998). Flavonoids also possess antioxidant activity
and they regulate the redox status and prevent damage
caused by oxidative stress. Protein Kinases are recog-
nised as encouraging target structures considering their
involvement in AD breakthrough pathways like patho-
physiological tau protein phosphorylation and amyloid
beta toxicity. The sound interdependence of tau phos-
phorylation and pathology has led to the search for Tau
protein kinase inhibitors such as GSK3- and Tyrosine
kinase Fyn, which phosphorylates tau and also plays a
causative role in amyloid pathway. Hereafter, acting as
potential therapeutic agents (Medina, 2018).
Nature has fascinated us with a lot of natural remedies
in the form of fruits, leaves, bark, vegetables, and nuts,
etc. The wide varieties of biologically active nutrients
existing in these natural products play a vital role in
defence and aid of various neurodegenerative diseases.
Flavonoids are an array of non-nutrient polyphenolic
compounds readily procured from plants. It was realized
that the competence of  avonoids to upgrade neurologi-
cal health was resolved by their antioxidant capability.
Flavonoids are endowed with numerous biological activ-
ities like anti-in ammatory, anticoagulant, anti-cancer,
anti-oxidants, and anti-spasmodic. There is an extensive
role of  avonoids and even their metabolites in differ-
ent signaling pathways by altering the phosphoryla-
tion state of target protein put forward their therapeutic
potential and bene cial in neurodegeneration(Spencer,
2007). Increasing evidence shows their ability to improve
brain function such as memory and learning by inter-
acting with cellular as well as molecular components of
the brain resulting in enhanced neuronal function and
induce neurogenesis (Spencer, 2010; Baptista et al. 2014).
A study has found the role of plant-derived com-
pounds such as myricetin and epicatechin-5-gallate in
abrogating heparin-induced cluster of tau into  laments
(Taniguchi et al. 2004). In drug discovery, the dominant
secondary metabolites (terpenoids, phenolics, and alka-
loids) are of probable remedial relevance. Certain  a-
vonoids such as indirubin and morin are capable of the
inhibiting the activity of GSK-3 beta and thereby block-
ing tau hyperphosphorylation. Kinases are involved
in tau phosphorylation and phosphatases reverse this
action. Thus,  avonoids also portray a crucial aspect in
modulating the activity of phosphatases (Baptista et al.
2014). Genistein (phytoestrogen), a bene cial intermedi-
ary for the treatment of AD as it imitates estrogen which
is involved in the development of memory and learning
along with its neuroprotective activities, (Hussain et al.
2018). It was found that eicosanoyl-5-hydroxytrypta-
mide (EHT), a naturally ocurring component of coffee
beans accelerates the activity of serine/threonine protein
phosphatase, PP2A and thus provide therapeutic ben-
e ts associated with AD (Asam et al. 2017).
The key events that lead to AD : Beta-amyloid toxic-
ity. The brain of a patient with the AD is characterized
by amyloid toxicity. Amyloid beta denotes peptides of
36-43 amino acids long processed from an amyloid pre-
cursor protein (APP) which is digested by beta secretase
and gamma secretase to yield amyloid beta (A ). This
peptide is found in brains of patients suffering from
Alzheimer’s (Murphy et al. 2010 Hamley, 2012, Sauer,
2017). Some processes include disruption of amyloid
beta aggregates, alterations in the precursor of amyloid
beta protein processing through the inhibition of beta-
secretase. Thus, modulating the beta-secretase activity is
the one suggested a therapeutic avenue to treat AD (Yin
et al. 2007). Certain  avonoids may guard to counter
the effect of Alzheimer’s disease by interrupting with
the generation of beta-amyloid peptides into neurotoxic
aggregates. It is a matter of contention that interfering
with the activity of beta and gamma-secretase enzymes
may disrupt their other functional roles besides playing
an important part in amyloidogenic pathways.
Thus such interference using secretase can result in
skin cancers and cognitive dysfunction (Kikuchi et al.
2017). The decades old theory which aims at implicating
beta amyloid as the leading cause of Alzheimer’s has
been questioned by a group of scientists. Researchers
have tried and failed to prevent Alzheimer’s using drugs
targeted at amyloid protein. Due to the lack of the
utility of amyloid--aspired approach in Phase III clini-
cal trials, it was prerequisite to conceive substitute drug
discovery strategies for alzheimer’s (Folch et al. 2016).
Solanezumab, a drug which acts on amyloid protein
failed some pivotal clinical trials. However, it is still
anonymous whether the disease is caused by plaques or
they are just the by- products (Ramsey, 2018).
A number of normal patients have been found with
amyloid deposists in their brain. It was anticipated that
Akanksha Joshi, Archit Sharma and Rajesh Kumar
amyloid beta deposition is an anomaly of aging and
does not correlate with the AD progression(Kametani et
al. 2018). Therefore there is a compulsive need to search
policies directed at reducing misfolded tau protien
is one of the disease-causing agents (Bruden et al. 2010).
Tau is liable to be the more superior target than the
amyloid as it coordinates ef ciently with cognitive
impairement, provided clinical symptoms are tangible
(Congdon et al. 2018).
For more than a decade, researchers have found ‘tau’
protein as one of the causes other than the Beta-amyloid
plaques (Underwood, 2016). Accordingly, tau hyperphos-
phorylation and accumulation of insoluble aggregates is
strongly related to reduce cognitive performance. Hence,
we can af rm that tau is a reliable marker of the neuro-
degenerative process (Fig.1). Incorporation of phosphate
groups into tau depends on; tau’s con rmation and
equity amidst the activity of kinases and phosphatases
(Kremer et al. 2011).
Changes in tau con rmation could lead to excessive
phosphorylation resulting in the formation of neurotoxic
aggregates and tau-mediated neurodegeneration (Dixit et
al. 2008). Tau is the member of family of proteins intri-
cated in stabilizing the microtubules. They are common
in neurons of Central Nervous System and also present at
low levels in CNS astrocytes and oligodendrocytes (Shin
FIGURE 1. Events that are involved in tau mediated neurodegeneration
a. Normal tau is hyperphosphorylated by; 1) Over activation of kinases such as GSK-3,
2) Inactivation of phosphatases such as PPA, PP2B
b.Tau hyperphosphorylation and accumulation of insoluble aggregates results in forma-
tion of paired helical fragments (PHF’s) followed by Neuro brillary tangles(NFT’s).
c. Formation of neurotoxic aggregates is the major hallmark in tau-mediated neurode-
d. Such a pathological event ultimately leads to Alzheimer’s.
e. recovery of abnormal tau into a normal like protein by using GSK-3 as a drug target-
Inhibiting GSK-3 with the aid of novel therapeutic phytocompounds is the most promis-
ing therapeutic intervention.
f. Targeting tau mediated neurodegeneration is one such approach to combat AD and
provide neuroprotection
Akanksha Joshi, Archit Sharma and Rajesh Kumar
et al.1991). The tau proteins have been formed as a result
of alternate splicing of MAPT ( microtubule -associated
protein tau) gene in humans and is positioned on chro-
mosome 17 (Goedert et al.1989; Jesus et al. 2016).
The hydrophilic nature of the tau protein and its exist-
ence as intrinsically disordered protein was unfolded by
many biophysical studies. (Porowska et al. 2014).One
of the critical function of tau protein is to prevent the
depolymerization of microtubules by regulating its sta-
bility in two ways: isoforms, and phosphorylation. On
the basis of the number of binding domains, six vari-
ants of tau protein (352-441 amino acids and apparent
molecular weight between 60-74kDa) exist in human
brain tissue (Martin et al. 2011). Out of six modi ca-
tions, three isoforms have 3 tubulin binding domains
and other three have 4 tubulin binding domains in the
C-terminal half of tau, (Guo et al. 2017).
The domain structure of tau is such that it’s positively
charged binding domain is located in carboxy-terminal
which binds to the microtubule which is negatively
charged. Tau is a phosphoprotein (i.e. posttranslationally
modi ed) with 79 probable Serine (Ser) and Threonine
(Thr) phosphorylation sites on the extended tau isoform.
It has been reported in a study that phosphorylation is
possible in about 30 sites in a normal tau protein. PKN,
a serine/threonine kinase is one such enzyme among the
plethora of kinases which regulates the phosphorylation
of tau (Billingsley et al. 1997). As revealed by primary
sequence analysis, the tau molecule has three major
domains: N-terminal (acidic), a proline-rich region,
C-terminal domain (basic). These domains are character-
ized on the basis of their amino acid character and even
on their microtubule interactions. Thus, tau protein acts
as a dipole with two domains having the opposite charge
(Kolarova et al. 2012; Porowska et al. 2014). Extreme
phosphorylation of the tau protein proceeds to the for-
mation of Paired helical fragments (PHF’s) due to the
loss of af nity with microtubules and they bind with
one another which further aggregates in neuro brillary
tangles via. Post-translational modi cations. Thus, there
is a strong correlation between abnormal phosphoryla-
tion and self-aggregation of tau (Guo et al. 2017)
When disorganized, this aside from being very solu-
ble protein forms remarkably insoluble tangles or aggre-
gates which commit to the number of neurodegenerative
disorders. The mutations in posttranslational modi ca-
tions are the main cause of this failure i.e. they form non-
functional aggregates. One of the studies demonstrated
that dephosphorylation of the hyperphosphorylated tau
converts abnormal tau protein into a normal like protein
which then regulates microtubule assembly(Iqbal et al.
2011). Therefore abrogating the abnormal tau and recov-
ery of the microtubule organization are the most prom-
ising therapeutic interventions to combat AD.
GSK-3 is encoded by two genes: GSK-3, located on
chromosome 19 and GSK-3, positioned on chromo-
some 2. GSK-3 is ubiquitously expressed in mammals
as well as in yeast (Medina et al. 2011). GSK3 mediates
the augmentation of phosphate molecules to serine and
threonine amino acid residues and for this reason termed
as serine/threonine protein kinase. The kinase domain
of these 2 isoforms are highly homologous ((Stambolic
et al. 1994) but are demarcated in the N- and C-termi-
nal regions. GSK3 has a molecular mass of 46-47 kDa
consisting of 433 and 420 amino acids in human and
mouse respectively. The protein contains an N-terminal
domain, a kinase domain, and a C-terminal domain. The
substrate Binding domain (BD) provides GSK-3 spe-
ci c binding sites for the tumor supressor p53 and other
protein complexes (Atlas of Genetics and Cytogenetics
in Oncology and Haematology). A number of protein
kinases are involved in tau phosphorylation such as
CdK5 (Cyclin-dependent Kinase 5), JNK (C-Jun amino-
terminal Kinase), CK1 (Casein Kinase1), Dyrk1A, AMPK
(Adenosine-monophosphate activated protein kinase),
MARK5 (Microtubule af nity-regulating Kinases), PKA
(Cyclic AMP-dependent protein Kinase), GSK-3 (Glyco-
gen Synthase Kinase-3) (Crews et al. 2010). But a study
has shown that 31% of the therapeutically favorable
phosphorylation sites of tau protein are phosphorylated
by GSK3 (Martin et al. 2013).
The classical approach to treat misfolding of tau pro-
tein provides inhibition of protein kinases (Glycogen
synthase kinase 3) which hosts tau phosphorylation.
According to the ‘GSK-3 hypothesis of AD’, tau hyper-
phosphorylation, memory impairment and enhanced
-amyloid production is due to the overexpression of
GSK-3, all of which are characteristic features of the
AD. If this hypothesis is consolidated then, inhibition of
GSK-3 by novel inhibitors provides a better pathway
against the effect of this destructing disorder (Hooper et
al. 2008). There are two isoforms of GSK-3 gene; GSK-3
alpha and GSK-3. GSK3 also exist as longer splice
variants (Mukai et al. 2002; Schaffer et al. 2003). More-
over, GSK-3 results in a neuronal decline in the AD
because of the fact that it is a causal mediator of apop-
tosis. Increased level of such protein eventuated in the
autopsy evaluation of brain of alzheimer’s victims (Pei et
al. 1997). It is also validated that a spatial and temporal
pattern of enhanced GSK-3 expression corresponds with
the evolvement of neuro brillary tangles proceeding
towards neurodegeneration (Leroy et al. 2002).
Drug research is an important tool in the  eld of medi-
cine. Utility of computers to anticipate the ef ciency
Akanksha Joshi, Archit Sharma and Rajesh Kumar
of binding of a set of small molecules or ligands with
the target is an important element of drug discovery
and developmental process. There is an ample realm of
software packages used to execute molecular docking
such as Dock, Autodock, GOLD, ICM, Glide, AutoDock
Vina, FlexX etc . Automated docking is generally used
for prognosis of biomolecular complexes, in structure
and function examination and in computer-aided drug
designing. A dozen of mechanism is available, con-
solidating varied energy evaluation methods. Due to
the enhanced docking speed, AutoDock 4.2 has been
widely used for virtual screening. It is the ultimate cur-
rent version which is based upon the Lamarckian genetic
algorithm, a hybrid algorithm comprising of both the
genetic as well as local search and is more enhanced and
accurate than previous version AD3.0. Unlike AD3.0,
Autodock 4.2.6 (henceforth AD4.2) and Auto Dock Vina
1.1.2 (henceforth AD Vina) have upgraded results and
improved elucidation, (Collignon et al. 2011, Nataraj et
al. 2017 and Alvarez et al. 2017).
Two main programs are involved in AutodockTools:
Autodock for docking of the ligand within the set of
grids (within the binding site) in the target protein and
Autogrid for selection of grid parameters, size of the
box, its location etc ( It is
particularly suitable for protein-ligand docking in which
we presume the pose and orientation of a small mol-
ecule when it is articled to a protein receptor. It is used
to select likely drug candidates. Typically, ligands are
drug candidates and the macromolecule is the protein
or receptor of the known three-dimensional structure.
In this docking simulation, the ligand being docked was
kept as  exible while target protein was kept as rigid.
The graphical user interface i.e. Autodock Tools was
used to prepare, run, analyzes the docking simulations.
Till date there are no such drugs/treatments available
that can cure AD completely. However, there are sev-
eral medications developed for Alzheimer’s disease that
can temporarily attenuate the symptoms. The Food and
Drug Administration (FDA), U.S. has af rmed two med-
ications-acetylcholinesterase inhibitors and Memantine.
Drugs such as tacrine, rivastigmine, galantamine, and
donepezilare are the widely used conventional drugs to
treat AD (Islam et al. 2013). Memantine is a dissocia-
tive hallucinogenic and anesthetic drug of the adaman-
tane class of chemicals that are currently used as an
FDA approved drug in the treatment of AD (www.alz.
org). Therefore, traditional drugs like memantine and
donepezil are being extendedly used as the reference in
molecular docking studies. Hence, the objective of even-
tual AD therapy is to discover such novel compounds
which can target the tau protein and so that can be uti-
lized for the recovery of neurodegenerative loss (Sch-
neide et al. 2008).
The study related to the AD is focused more towards
the traditional medicinal plants and its components such
as Withania somnifera (Ashwagandha), Celastrus pan-
iculatus (Jyotismati), Convolvulus pluricaulis (Shankh-
pushpi), Bacopa monnieri (Brahmi). By analyzing the
binding energies of various ligands such as acacatechin,
catechin, galangin, scopoletin, silibinin, memantine (as
standard), it was observed that  avonoids exhibit bind-
ing energy scaled between 7.07 kcal/mol to -4.85 kcal/
mol. Silibinin demonstrate prominent binding energy
-7.07 kcal/mol than the standard memantine (-5.89 kcal/
mol) (Madeswaran et al. 2013). A phytocompound, Cat-
echin (with binding energy -9.7 kcal/mol) was shown
to be the potent target of GSK-3 and showed the same
drug-likeness as conventional drug Donepzil (with bind-
ing energy-8.9kcal/mol), (Alam et al. 2017).
Withania somnifera, a potential inhibitor of GSK-3
Withania somnifera commonly called Ashwagandha,
Indian ginseng and wind cherry have been recognizes as
an important herb in Indigenous and ayurvedic medical
system. Historically, the plant has been used therapeuti-
cally for boosting the brain function including memory
retrieval. It has a cognition promoting effect in adults
and children (Singh et al. 2011). It consists of two com-
ponents: withanolides and withanamides. Withanolide
A is extracted from the roots of the plant and promotes
antioxidant properties that protect nerve cells from
harmful free radicals. Many clinical trials and exces-
sive research on animals support the use of Ashwagan-
dha for anxiety, cognitive and neurological disorders (
Rajasekar et al. 2011). Withanolides have also been used
for the treatment of AD (Khan et al. 2016). Withanolide
A is used as an inhibitor of acetylcholinesterase activity
and reduces beta-amyloid protein formation. Also, it has
been involved in the regeneration of pre and postsynap-
tic neurons. Instead of the root extract, a study also sug-
gested fruits and leaves of Egyptian plant have strong
antioxidant activity (Mahrous et al. 2017)
Several new therapeutic approaches are currently under
investigation which aims at targeting proteins such as
Apolipoprotein E which is also responsible for the accu-
mulation and hyperphosphorylation of tau. Anti-tau
immunotherapeutic agents have gained much focusdue
to their speci city and selectivity to combat AD. But a
longer follow up period might be required to test the
safety and ef cacy as the results were promising .More-
over targeting either tau or amyloid beta individually is
Akanksha Joshi, Archit Sharma and Rajesh Kumar
not apparently the satisfactory approach and therefore,
combinational therapies might be thought of as a new
proposal, (Coman et al. 2017 Bittar et al. 2018).
Drug research is of utmost importance in the  eld of
medicine. Consequently, the use of computers to foresee
the ef ciency of binding of a set of molecules or ligands
with the target is an important element of drug devel-
opment process.To explore potent and effective drugs
for the treatment of AD, different phytocompounds
were compared against the standard using Autodock4.
Appropriate ligands were docked into the active site of
the receptor GSK-3 and analyzed for the effective pro-
tein-ligand interactions. Therefore molecular docking
identi ed many more promising, ef cacious, selective
new drugs against Alzheimer’s reducing the time span
of complex drug discovery process. Appropriate experi-
mental evidences such as ADMET analysis which tes-
ti es absorption, penetration and toxicity may also be
considered further as a lead in drug discovery process.
The authors are thankful to the Department of Biotech-
nology, University Institute of Engineering and Technol-
ogy, Kurukshetra (U.I.E.T) for providing the space and
resources for this work.
Authors state no con ict of interest. All authors have
read the journal’s Publication ethics and publication
malpractice statement available at the journal’s website
and hereby con rm that they comply with all its parts
applicable to the present scienti c work.
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