Alzheimer disease (AD) is a neurodegenerative disorder including continuously progressive cognitive and functional deficits as well as behavioral changes and is related with amassing of amyloid and tau depositions in the brain. Subjective side effects of AD most ordinarily incorporate deficits in short-term memory, executive and visuospatial dysfunction, and praxis. Mammalian methionine sulfoxide reductase A is encoded by a single gene and is found in both cytosol and mitochondria. Biologically active compounds from different plants have been used to treat various ailments. In the present study, mitochondrial peptide methionine sulfoxide reductase protein sequence from Homo sapiens was retrieved from UniProt and selected structure of the peptide methionine sulfoxide reductase from Escherichia coli (Protein Data Bank [PDB] id: 1FF3) was used as template. The homology model was developed by using Modeller 9.20 version. Molecular docking studies were performed using Autodock4.2. 20 natural compounds were docked against modeled protein. All the compounds exhibited good binding energy. Campesterol showed with lesser energy of −9.0 Kcal/mol.
Molecular Modeling of Metalloreductase STEAP2 Protein and Docking Interaction...BRNSS Publication Hub
This gene is an individual from the STEAP family and encodes a multipass film protein that confines to the Golgi complex, the plasma layer, and the vesicular cylindrical structures in the cytosol. A very comparative protein in mouse has both ferrireductase and cupric reductase action and invigorates the cell take-up of both iron and copper in vitro. Expanded transcriptional articulation of the human quality is related with prostate malignant growth movement. Substitute transcriptional graft variations, encoding distinctive isoforms, have been described. Therefore, in the present study, we generated a precise three-dimensional (3D) model of metalloreductase STEAP2 protein using MODELLER 9.21 and validated its structure using PROCHECK software. Modeled protein contains more than 94.5% of amino acids in core region. We interpreted the action of natural compounds docking against the modeled metalloreductase STEAP2 protein. Three compounds (ginkgetin, medicagenin, and erybraedin A) showed lower binding affinity values toward metalloreductase STEAP2 protein compared to mitoxantrone, abiraterone acetate, apalutamide, enzalutamide, and flutamide. Ginkgetin exhibited the lowest binding energy of −9.10 kcal/mol with interacting Trp212 and Thr210. All the 17 compounds showed excellent binding energies than standard drugs for the modeled metalloreductase STEAP2 protein. These computational studies can be helpful to discover novel drug candidates.
Protein aggregation is the most discussed topic as it is being linked to many neurodegenerative diseases. Here, in these slides I have tried to explain about protein aggregation and its mechanism.
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the fuction of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function. The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases), include such diseases as Alzheimer's disease, Parkinson's disease, prion disease, type 2 diabetes, amyloidosis, and a wide range of other disorders .
Molecular Modeling of Metalloreductase STEAP2 Protein and Docking Interaction...BRNSS Publication Hub
This gene is an individual from the STEAP family and encodes a multipass film protein that confines to the Golgi complex, the plasma layer, and the vesicular cylindrical structures in the cytosol. A very comparative protein in mouse has both ferrireductase and cupric reductase action and invigorates the cell take-up of both iron and copper in vitro. Expanded transcriptional articulation of the human quality is related with prostate malignant growth movement. Substitute transcriptional graft variations, encoding distinctive isoforms, have been described. Therefore, in the present study, we generated a precise three-dimensional (3D) model of metalloreductase STEAP2 protein using MODELLER 9.21 and validated its structure using PROCHECK software. Modeled protein contains more than 94.5% of amino acids in core region. We interpreted the action of natural compounds docking against the modeled metalloreductase STEAP2 protein. Three compounds (ginkgetin, medicagenin, and erybraedin A) showed lower binding affinity values toward metalloreductase STEAP2 protein compared to mitoxantrone, abiraterone acetate, apalutamide, enzalutamide, and flutamide. Ginkgetin exhibited the lowest binding energy of −9.10 kcal/mol with interacting Trp212 and Thr210. All the 17 compounds showed excellent binding energies than standard drugs for the modeled metalloreductase STEAP2 protein. These computational studies can be helpful to discover novel drug candidates.
Protein aggregation is the most discussed topic as it is being linked to many neurodegenerative diseases. Here, in these slides I have tried to explain about protein aggregation and its mechanism.
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the fuction of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function. The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases), include such diseases as Alzheimer's disease, Parkinson's disease, prion disease, type 2 diabetes, amyloidosis, and a wide range of other disorders .
Protein synthesis and disposal occur in highly regulated manner. In cells protein folding is assisted by special kind of proteins called as molecular chaperones and disturbances in protein quality control leads to deadly diseases
How different diseases originate with slightest changes in proteins. Understanding ALS , Parkinson, Alzhiemer , Taupathies development which may lead to their treatment!
Plasma phospholipids identify antecedent memory impairment in older adultsJosé Luis Moreno Garvayo
En este trabajo publicado en la revista Nature medicine el pasado mes de marzo, el equipo del Dr. Federoff plantea un novedoso enfoque que consiste en analizar un grupo de diez fosfolípidos para la detección de la enfermedad de Alzheimer antes de la manifestación clínica de los síntomas.
Detection of misfolded aβ oligomers for sensitive biochemical diagnosis of Al...José Luis Moreno Garvayo
El equipo del Dr. Claudio Soto de la Universidad de Texas ha conseguido demostrar que son capaces de detectar pequeños fragmentos de proteínas mal plegadas, los precursores de las placas seniles, que pueden estar circulando por nuestro cuerpo durante años o décadas antes de que surjan los primeros síntomas de la enfermedad de Alzheimer
N-glycosylation of ICAM-2 is required for ICAM-2- mediated complete suppressi...Enrique Moreno Gonzalez
Cell adhesion molecules (CAMs) are expressed ubiquitously. Each of the four families of CAMs is comprised of glycosylated, membrane-bound proteins that participate in multiple cellular processes including cell-cell communication, cell motility, inside-out and outside-in
signaling, tumorigenesis, angiogenesis and metastasis. Intercellular adhesion molecule-2 (ICAM-2), a member of the immunoglobulin superfamily of CAMs, has six N-linked glycosylation sites at amino acids (asparagines) 47, 82, 105, 153, 178 and 187. Recently, we demonstrated a previously unknown function for ICAM-2 in tumor cells. We showed that ICAM-2 suppressed neuroblastoma cell motility and growth in soft agar, and induced a juxtamembrane distribution of F-actin in vitro. We also showed that ICAM-2 completely suppressed development of disseminated tumors in vivo in a murine model of metastatic NB.
These effects of ICAM-2 on NB cell phenotype in vitro and in vivo depended on the interaction of ICAM-2 with the cytoskeletal linker protein α-actinin. Interestingly, ICAM-2
did not suppress subcutaneous growth of tumors in mice, suggesting that ICAM-2 affects the metastatic but not the tumorigenic potential of NB cells. The goal of the study presented here was to determine if the glycosylation status of ICAM-2 influenced its function in neuroblastoma cells.
Inhibition of Aldose Activity by Essential Phytochemicals of Cymbopogon citra...CSCJournals
The ambiguity of whether aldose reductase, an enzyme of polyol pathway, is linked to diabetes and its complication has been receded based on the recent studies made on the inhibition of its (Aldose reductase) activity. In our current study, we have used an in silico approach (molecular docking) to analyze the effect of essential phytochemicals obtained from Cymbopogon citratus on the aldose reductase activity. C.citratus is grown extensively in tropical countries including India for perfumery and pharmaceuticals. The essential phytochemicals of C.citratus like Myrcene, Citral, and Geraniol have been used as ligand for the molecular docking analysis with Aldose reductase as receptor. The docking analysis showed Myrcene, with binding energy of -8.76 Kcal/mol is best amongst Citral and Geraniol which are having binding energies of -7.24 Kcal/mol and -7.93 Kcal/mol respectively for inhibiting the activity of Aldose reductase.
Protein synthesis and disposal occur in highly regulated manner. In cells protein folding is assisted by special kind of proteins called as molecular chaperones and disturbances in protein quality control leads to deadly diseases
How different diseases originate with slightest changes in proteins. Understanding ALS , Parkinson, Alzhiemer , Taupathies development which may lead to their treatment!
Plasma phospholipids identify antecedent memory impairment in older adultsJosé Luis Moreno Garvayo
En este trabajo publicado en la revista Nature medicine el pasado mes de marzo, el equipo del Dr. Federoff plantea un novedoso enfoque que consiste en analizar un grupo de diez fosfolípidos para la detección de la enfermedad de Alzheimer antes de la manifestación clínica de los síntomas.
Detection of misfolded aβ oligomers for sensitive biochemical diagnosis of Al...José Luis Moreno Garvayo
El equipo del Dr. Claudio Soto de la Universidad de Texas ha conseguido demostrar que son capaces de detectar pequeños fragmentos de proteínas mal plegadas, los precursores de las placas seniles, que pueden estar circulando por nuestro cuerpo durante años o décadas antes de que surjan los primeros síntomas de la enfermedad de Alzheimer
N-glycosylation of ICAM-2 is required for ICAM-2- mediated complete suppressi...Enrique Moreno Gonzalez
Cell adhesion molecules (CAMs) are expressed ubiquitously. Each of the four families of CAMs is comprised of glycosylated, membrane-bound proteins that participate in multiple cellular processes including cell-cell communication, cell motility, inside-out and outside-in
signaling, tumorigenesis, angiogenesis and metastasis. Intercellular adhesion molecule-2 (ICAM-2), a member of the immunoglobulin superfamily of CAMs, has six N-linked glycosylation sites at amino acids (asparagines) 47, 82, 105, 153, 178 and 187. Recently, we demonstrated a previously unknown function for ICAM-2 in tumor cells. We showed that ICAM-2 suppressed neuroblastoma cell motility and growth in soft agar, and induced a juxtamembrane distribution of F-actin in vitro. We also showed that ICAM-2 completely suppressed development of disseminated tumors in vivo in a murine model of metastatic NB.
These effects of ICAM-2 on NB cell phenotype in vitro and in vivo depended on the interaction of ICAM-2 with the cytoskeletal linker protein α-actinin. Interestingly, ICAM-2
did not suppress subcutaneous growth of tumors in mice, suggesting that ICAM-2 affects the metastatic but not the tumorigenic potential of NB cells. The goal of the study presented here was to determine if the glycosylation status of ICAM-2 influenced its function in neuroblastoma cells.
Inhibition of Aldose Activity by Essential Phytochemicals of Cymbopogon citra...CSCJournals
The ambiguity of whether aldose reductase, an enzyme of polyol pathway, is linked to diabetes and its complication has been receded based on the recent studies made on the inhibition of its (Aldose reductase) activity. In our current study, we have used an in silico approach (molecular docking) to analyze the effect of essential phytochemicals obtained from Cymbopogon citratus on the aldose reductase activity. C.citratus is grown extensively in tropical countries including India for perfumery and pharmaceuticals. The essential phytochemicals of C.citratus like Myrcene, Citral, and Geraniol have been used as ligand for the molecular docking analysis with Aldose reductase as receptor. The docking analysis showed Myrcene, with binding energy of -8.76 Kcal/mol is best amongst Citral and Geraniol which are having binding energies of -7.24 Kcal/mol and -7.93 Kcal/mol respectively for inhibiting the activity of Aldose reductase.
Citicoline is a nootropic agent. It is used in the treatment of brain insufficiency and other neurological disorders such as brain stroke, trauma, and Parkinson’s disease. This review article represents summarized results of published analytical methods in the literature for the determination of citicoline in biological and pharmaceutical formulations. Various techniques such as spectrophotometry, liquid chromatography (LC), high-performance LC, ultra performance LC, gas chromatography, nuclear magnetic resonance, and hydrophilic interaction LC method were reported.
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2013 2nd International Conference on Environment, Energy and Biotechnology (ICEEB 2013)
2013 2nd International Conference on Chemical and Process Engineering (ICCPE 2013)
2013 2nd Journal Conference on Environmental Science and Development (JCESD 20132nd)
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2. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 53
susceptible to oxidation in vivo, particularly under
conditions of oxidative stress.[8]
In the present study, in silico studies were
performed due to the absence of crystal structure
for mitochondrial peptide methionine sulfoxide
reductase protein. The homology model of the
protein was developed using Modeller 9.20
and validated using Procheck. To study the
binding affinity of protein-ligand and molecular
interactions of mitochondrial peptide, methionine
sulfoxide reductase docking studies were
performed using Autodock4.2.
METHODOLOGY
Sequence alignment and structure prediction
The amino acid sequence of mitochondrial
peptide methionine sulfoxide reductase (UniProt
accession number: Q9UJP8) from the species
Homo sapiens was retrieved from the UniProtKB
database.[9]
A Basic Local Alignment Search
Tool (BLAST) search was performed to select
the template. Structure of the peptide methionine
sulfoxide reductase from Escherichia coli (PDB
ID: 1FF3_A)[10]
was selected as a template. The
three-dimensional structure was generated using
Modeller 9.20. The respective templates were
retrieved from protein database like PDB.[11]
When choosing the template, it is important to
consider the sequence identity and resolution of
the template. When both parameters are high, the
resulting model would be sufficiently good to
allow structural and functional research.
MODELLER 9.20 was then used to generate
satisfactory models; an automated approach to
homology modeling by satisfaction of spatial
restraints. Sequence alignments using the protein
and template sequences was then carried out using
platforms such as Clustal X and Clustal
W[12]
[Figure
1]. Homology models for the chosen
protein were then constructed using modeler
programs like Modeller 9.20.[13]
After manually
modifying the alignment input file in MODELLER
9.20 to match the query and template sequence,
20 models were generated. The best model is
determined by the lowest value of the Modeller
objective function. The stereochemical quality
of the given models was then evaluated using
software like PROCHECK,[14]
and the model
can be used for further structural or functional
study. PROCHECK generated a Ramachandran
plot which explains residue by residue listing
that facilitates the in-depth calculation of Psi/Phi
angles and the backbone conformation of the
models. The root-mean-square deviation (RMSD)
was calculated by superimposing (1FF3_A) over
the generated model to access the accuracy and
reliability of the generated model using SPDBV.[15]
Docking methodology
Identification of active site pockets: The active
site prediction was carried out using Tripo’s
Sybyl6.7.[16]
It showed three active site pockets.
The amino acids in pocket one were Asn140,
Tyr219, Gly221, Leu222, Gly223, Cys74, Ala78,
and Lys81.
In total, 20 natural compounds were retrieved
from NCBI. All the molecules were sketched in
sybyl6.7 and minimized by adding Gasteiger-
Huckel charges and saved in.mol2 format.
Molecular docking studies were performed
on all the natural compounds separately using
AutoDock4.2[17]
program, using the Lamarckian
genetic algorithm, and empirical free energy
function was implemented. Initially, the modeled
mitochondrial peptide methionine sulfoxide
reductase protein was loaded and hydrogens were
added before saving it in PDBQT format. Later,
Figure 1: Sequence alignment of mitochondrial peptide methionine sulfoxide reductase protein and template 1FF3
3. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 54
the ligand was loaded and conformations were set
and saved in PDBQT format. The grid parameters
were selected and calculated using AutoGrid. For
all the dockings, a grid-point spacing of 0.375
Å was applied and grid map with 60 × 60 × 60
points was used. X, Y, and Z coordinates were
selected on the basis of the amino acids present
in the active site predicted in sybyl6.7 biopolymer
module. Default parameters were used to run the
Autodock.
RESULTS AND DISCUSSION
Homology modeling and model evaluation
The present study reports that the template
protein (PDB ID: 1FF3_A) having high degree
of homology with Q9UJ68 protein was used as a
template with good atomic resolution of its crystal
structure. The target sequence of mitochondrial
peptide methionine sulfoxide reductase (UniProt
accession number: Q9UJ68_Human) bearing
235 amino acid residues was retrieved from
the UniProt protein sequence database with
Accession No. Q9UJ68. Using BLAST, PDB ID
1FF3_A was identified and selected as a template
to predict the model. The structure was modeled
using Modeller9.20. The generated structure
was validated using the protein structure and by
PROCHECK. The generated model showed that
90.3% of amino acid residues in core region with
176 amino acids, 8.2% of amino acid residues
in additionally allowed region having 16 amino
acids, 1.5% of the amino acid residues in the
generously allowed region with three amino acids,
and there are no amino acids present in disallowed
region. The template PDB shows that 90.1% of
amino acids in core region, 9.9% of the amino
acid residues in additionally allowed region, and
there are no amino acid residues in generously
allowed region and disallowed region. Cartoon
model of secondary structure of the modeled
protein is shown in Figure 2 and Ramachandran
plot is shown in Figure 3. RMSD was calculated
for template and generated model using SPDBV.
Both the models were loaded and superimposed
using the alpha carbon and RMSD was calculated.
It showed RMSD of 0.32Å, which indicates
that the generated model shows similarity to the
template [Figure 4].
Molecular docking results
Molecular docking is the most extensively used
method for the calculation of protein-ligand
interactions. It is an efficient method to predict the
potential ligand interactions. In the present study,
the native plant secondary metabolites (ligands)
have been identified as potent mitochondrial
peptide methionine sulfoxide reductase inhibitors.
AutoDock4.2 uses (genetic algorithm) binding
free energy assessment to assign the best binding
conformation. Further, the activity of docked
ligand molecules was compared to that of standard
drugs which were controls. In total, 20
natural
compounds were docked against modeled
mitochondrial peptide methionine sulfoxide
reductase.
However, the compounds campesterol and
xanthostigmine showed better interactions
and lower free energy values, indicating more
thermodynamically favored interactions. Both the
compounds exhibited binding energy of −9.0
Kcal/mol. Specifically, campesterol exhibited
the highest binding energy of value −9.09 K.cal/
mol while interacting with Glu117 and artocarpin
exhibited binding energy of −8.54 K.cal/mol
with interacting Glu117. When compared to the
standard drugs, i.e. memantine, donepezil, tacrine,
and xanthostigmine campesterol exhibited highest
binding energy. Xanthostigmine exhibited binding
energy of −9.00 Kcal/mol while interacting with
Tyr105. All the compounds showed good binding
energy with modeled protein. Three compounds
exhibited binding energy −8.00 Kcal/mol, six
compounds exhibited binding energy of −7.00
Figure 2: The cartoon model of mitochondrial peptide
methionine sulfoxide reductase modeled protein
4. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 55
KCal/mol. The natural compounds with their
corresponding interactions and binding energies
are shown in Table 1 and Figure 5.
CONCLUSION
The sequence obtained from UniProt does not
contain the crystal structure (three-dimensional
structure) in the PDB database. The crystal
structure was built by homology modeling using
Modeller 9.20. Modeled protein was validated
using Procheck. The generated model showed
90.3% of amino acid residues in the most favored
region. The generated model was then docking
with 20 natural compounds and also docked
already existing drugs as controls. Natural
compounds showed better binding energies than
already existing drugs. Campesterol exhibited
highest binding energy of −9.09 Kcal/mol with
interacting Glu117. The study explains that natural
compounds are more potent than already existing
drugs for Alzheimer’s.
Figure 3: Ramachandran plot of the modeled mitochondrial peptide methionine sulfoxide reductase protein exhibited
90.3% amino acid residues in the most favored region
6. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 57
5) 6)
7)
8)
9)
10)
11) 12)
13) 14)
7. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 58
15) 16)
17) 18)
19) 20)
21) 22)
8. Patel, et al.: In Silico modeling and docking studies on methionine sulfoxide reductase a protein
IJPBA/Jan-Mar-2019/Vol 10/Issue 1 59
23) 24)
Figure 4: Superimposed model of modeled mitochondrial
peptide methionine sulfoxide reductase protein and
template protein
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