Download Virtual Screening of Active Compounds of Valeriana wallichii

2011 International Conference on Bioscience, Biochemistry and Bioinformatics
IPCBEE vol.5 (2011) © (2011) IACSIT Press, Singapore
Virtual Screening of Active Compounds of Valeriana wallichii, Acorus Calamus and
Asparagus Racemosus with Schizophrenic Proteins COMT & GRM3
Preenon Bagchi
Waheeta Hopper
Research Scholar, Dept. of Bioinformatics, School of
Bioenginering, SRM University, Kattankulathur,
Tamil Nadu, India
e.mail: [email protected]
Professor & Head, Dept. of Bioinformatics,
School of Bioenginering, SRM University,
Kattankulathur, Tamil Nadu, India
e.mail: [email protected]
involved with personality, planning, inhibition of behaviors,
abstract thinking, emotion, and working (short-term)
memory. To function efficiently, the prefrontal cortex
requires signalling by neurotransmitters such as dopamine
and norepinephrine. The characteristic signs and symptoms
of 22q11.2 deletion syndrome result from a deletion of a
small piece of chromosome 22. A loss of one copy of the
COMT gene leads to abnormal regulation of catechol-omethyltransferase levels in the brain. Researchers believe
that changes involving this enzyme in the prefrontal cortex
may help to explain the increased risk of behavioral
problems and mental illness associated with 22q11.2 deletion
syndrome. People with 22q11.2 deletion syndrome are more
likely to develop schizophrenia, depression, anxiety, and
bipolar disorder than people without the condition [3, 4].
Abnormally high dopaminergic transmission has been linked
to psychosis and schizophrenia. Increased dopaminergic
functional activity, specifically in the mesolimbic pathway,
is found in schizophrenic individuals. Anti-psychotic
medications act largely as dopamine antagonists, inhibiting
dopamine at the receptor level, and thereby blocking the
effects of the neurochemical in a dose-dependent manner.
Inhibitors of alternative metabolic route for dopamine by
catechol-o-methyl transferase are also used [5].
GRM3: Glutamate is the major excitatory
neurotransmitter in the mammalian central nervous system.
Imbalances in glutamatergic function have been implicated
in neuronal death following ischemia, in hypoglycemia or
anoxia, in epilepsy, and in neurodegenerative disorders.
Glutamate actions are mediated by glutamate receptors
which fall into 2 distinct classes: ionotropic and
metabotropic receptors. Ionotropic glutamate receptors are
ligand-gated ion channels whose responses to selective
agonists define the N-methyl-D-aspartate, alpha-amino-3hydroxy-5-methyl-isoxasole-4-propionate,
and
kainate
subtypes. The metabotropic glutamate receptors, which are
coupled through GTP-binding proteins to second-messenger
pathways, can be involved in the stimulation of
phospholipase C, the presynaptic inhibition of glutamate
release, the closure of cation channels in retinal on bipolar
cells, and the modulation of adenylate cyclase. The eight
distinct metabotropic glutamate receptors that have been
identified can be classified into three groups according to
their sequence similarities, pharmacologic properties, and
Abstract—Gene mutation in COMT and GRM3 are one of the
causes for Schizophrenia. Their amino acid sequences are
retrieved; their 3D structures were determined by homology
modelling. The 3D structures of the compounds of Valeriana
wallichii, Acorus calamus and Asparagus racemosus were
sketched using Chemsketch & converted to 3D. These
compounds were virtually screened with COMT and GRM3
proteins. COMT protein had good interaction with baldrinal
from V. wallichii, calamusenone from A. calamus and
racemosol from A. racemosus. GRM3 protein had good
interaction with homobaldrinal from V. wallichii, galangin
from A. calamus and racemosol from A. racemosus.
Keywords-Schizophrenia, Homology Modelling, Valeriana
wallichii, Acorus calamus, Asparagus racemosus, metabotropic
glutamate receptor, Virtual Screening.
I.
INTRODUCTION
Schizophrenia is a severe mental disorder characterized
by two kinds of symptoms; positive psychotic symptoms thought disorder, hallucinations, delusions, and paranoia and negative symptoms – impairment in emotional range,
energy, and enjoyment of activities. Schizophrenia is a
particular form of psychosis, a term encompassing several
severe mental disorders that result in the loss of contact with
reality along with major personality derangements. Presently
researchers suspect a genetical cause for schizophrenia along
with environmental basis. Psychosocial factors play an
important role in the formation & development of this
disorder. Individual as well as family counseling is necessary
to help patients to lead a normal social life. Cognitivebehavioral approach along with proper medication can pave
a path for curing this disorder. The cause of Schizophrenia is
multi-gene mutation (including environmental factors) [1, 2].
In this work COMT and GRM3 genes are virtually screened
with the compounds of Valeriana wallichii, Acorus calamus
and Asparagus racemosus.
COMT: Catechol-O-methyltransferase catalyzes the
transfer of a methyl group from s-adenosylmethionine to
catecholamines, including the neurotransmitters dopamine,
epinephrine,
and
norepinephrine.
Catechol-omethyltransferase is particularly important in the prefrontal
cortex of the brain, which organizes and coordinates
information from other parts of the brain. This region is
15
preferred signal transduction mechanism. The human genes
for mGlu2 and mGlu3 receptors have been localized to
chromosomes 3 (p21.1) and 7 (7q21.1-q21.2) respectively.
The main glutamate transporter GLT-1 is responsible for
clearing synaptically released glutamate from the
extracellular space and contributes to the shaping of
glutamatergic transmission [6, 7].
Valeriana wallichii: Valeriana wallichii commonly
known as Indian valerian is one of the important plant
species of commerce. It is native to India (Himalayas). It
grows wild in the temperate Himalaya at an altitude of 15003000 m and is an ingredient of Indian systems of herbal
medicine. It is used in India for its benefits in calming down
the nervous system. It relieves stress and anxiety and also
fights depression. Valeriana is nature's best stress busting
herb. Valeriana continues to be a safe sedative/hypnotic
choice for patients with mild to moderate insomnia. The
compounds identified from the plant are acetoxy valerenic
acid, acevaltrate, baldrinal, bornyl acetate, bornyl isovalerate,
fenchene, β-sitosterol, calarene, homobaldrinal, isovaltrate,
valeranone, valerenal, valerenic acid, valepotriate, valtrate,
valtroxal and xanthorrhizol (Fig. 1) [8].
Acorus calamus: Acorus calamus or sweet flag has been
long known for its medicinal value and is cultivated in Asia
for this reason. The rhizome contains aromatic oil that has
been used medicinally since ancient times. The rhizome
possesses anti-spasmodic, carminative and anthelmintic
properties and is also used for the treatment of epilepsy,
mental ailments, chronic diarrhea, dysentery, bronchial
catarrh, intermittent fevers and glandular and abdominal
tumors. The compounds identified from the plant are 1α, 2β,
3γ,
19α-tetrahydroxyurs-12en-28-oicacid-28-O{-β-Dglucopyranosyl (1→2)} β- D- galactopyranoside, 2,3dihydro-4,5,7-trimethoxy-1ethyl-2-methyl-3-(2,4,5trimethoxy phenyl)indene, 2,4,5-trimethoxy benzaldehyde,
2,6-diepishyobunone, 3β, 22α, 24, 29-tetrahydroxyolean-12en-3-O-{-β-D-arabinosyl(1→3)}-β-D-arabinopyranoside, 4,
5, 8-trimethoxyxanthone-2-O-β-D-glucopyranosyl(1→2)-Oβ-D-galactopyranoside,
acoradin,
acoragermacrone,
acoramone(1,2,4
–trimethoxy-5(2-propanoyl)
benzene,
β-sitosterol,
Calamusenone,
cis-asarone(cis-1,2,4
–
trimethoxy-5(2propenyl)
benzene,
galangin,
γ-cis-asarone(cis-1,2,4 –trimethoxy-5(2- propenyl) benzene,
isoeugenol methyl ether, isocalamendiol
limonene,
preisocalamendiol, shyobunone
thujane and Z3-(2,4,5-trimethoxy phenyl)-2-propenal. (Fig. 2) [9].
Asparagus racemosus: Asparagus racemosus has been
used in India for thousands of years for its therapeutic and
tonic properties. Due to its multiple uses, the demand for
Asparagus is constantly on the rise. The plant has been
shown to aid in the treatment of neurodegenerative disorders
and in alcohol abstinence-induced withdrawal symptoms.
The genus Asparagus includes about 300 species around the
world. The genus is considered to be medicinally important
because of the presence of steroidal saponins and sapogenins
in various parts of the plant. Out of the 22 species of
Asparagus recorded in India, Asparagus racemosus is the
one most commonly used in traditional medicine. The
compounds identified from the plant are asparagamine,
racemosol, sarsasapogenin and shatavarin (Fig 3) [10].
II.
METHODOLOGY
The COMT sequence with accession number
NP_009294.1 was taken the National Center for
Biotechnology Information (NCBI) and using BLAST search
engine against Protein Data Bank (PDB) the following
templates were selected and their crystal structures were
downloaded from PDB.
•
3BWMA: Crystal Structure Of Human Catechol OMethyltransferase with Bound Sam And Dnc. from
Homo Sapiens [identity-96%]
• 2ZLBA: Crystal Structure Of Apo Form Of Rat
Catechol-O-Methyltransferase [identity-61%]
• 1JR4A: Catechol O-Methyltransferase BisubstrateInhibitor Complex from Rattus Norvegicus
[identity-98%]
The COMT sequence is aligned with 3BWMA, 2ZLBA
and 1JR4A.
_aln.pos
3BWMA
2ZLBA
1JR4A
COMT
_consrvd
10
20
30
40
50
60
-GDTKEQRILNHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLELGAY
--DTKEQRILRYVQQNAKPGDPQSVLEAIDTYCTQKEWAMNVGDAKGQIMDAVIREYSPSLVLELGAY
--DTKEQRILRYVQQNAKPGDPQSVLEAIDTYCTQKEWAMNVGDAKGQIMDAVIREYSPSLVLELGAY
MGDTKEQRILNHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLELGAY
******** * * * ** *********** ********** ** * **** * ** ******
_aln.p
3BWMA
2ZLBA
1JR4A
COMT
_consrvd
70
80
90
100
110
120
130
CGYSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKYDVDTLD
CGYSAVRMARLLQPGARLLTMEMNPDYAAITQQMLNFAGLQDKVTILNGASQDLIPQLKKKYDVDTLD
CGYSAVRMARLLQPGARLLTMEMNPDYAAITQQMLNFAGLQDKVTILNGASQDLIPQLKKKYDVDTLD
CGYSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKYDVDTLD
************ ***** * * *** ***** * *** ****
***** **************
_aln.pos
3BWMA
2ZLBA
1JR4A
COMT
_consrvd
140
150
160
170
180
190
200
MVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFECTHYQSFLEYREVV
MVFLDHWKDRYLPDTLLLEKCGLLRKGTVLLADNVIVPGTPDFLAYVRGSSSFECTHYSSYLEYMKVV
MVFLDHWKDRYLPDTLLLEKCGLLRKGTVLLADNVIVPGTPDFLAYVRGSSSFECTHYSSYLEYMKVV
MVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFECTHYQSFLEYREVV
******************* **************** ** ***** ***** ****** * *** **
_aln.pos
3BWMA
2ZLBA
1JR4A
COMT
_consrvd
210
220
DGLEKAIYKGP-----DGLEKAIYQG------DGLEKAIYQG------DGLEKAIYKGPGSEAGP
******** *
Based on this data the 3D structure of COMT protein was
generated by modeler.
Also, GRM3 sequence with accession number
AAA52568 was taken from NCBI. Using BLAST search
engine against PDB , the following templates were selected:
• 3KG2A: Ampa subtype ionotropic Glutamate
Receptor in complex with competitive antagonist
from Rattus Norvegicus [identity-89%]
• 3H6GA: Crystal structure of the Glur6 amino
terminal domain dimer assembly from Rattus
Norvegicus [identity-43%]
• 1YAEA: Structure of The kainate receptor subunit
Glur6 agonist binding domain complexed with
domoic acid from Rattus Norvegicus [identity-43%]
The crystal structure of the above templates were
downloaded from PDB.
_aln.pos
3KG2A
3H6GA
1YAEA
16
10
20
30
40
50
60
-------------------------------------------NSIQIGGLFPRGADQEYSAFRVGMV
------------------------------------------------------------------------------------------------------PANITDSL-------------------------
The 3d structures of the active components of Valeriana
wallichii, Acorus calamus and Asparagus racemosus were
drawn using chemsketch and saved as *.mol file.
Virtual Screening of the compounds of Valeriana
wallichii, Acorus calamus and Asparagus racemosus was
done with COMT & GRM3 proteins using Maestro9.1
software.
The proteins were prepared using Protein Preparation
Wizard of Maestro9.1 software, optimized and minimized.
The receptor grid was set up and active site residues for the
proteins were assigned by using the Receptor Grid
Generation panel.
The grid region assigned for COMT protein was TRP38,
MET40, ASP141, TRP143, LYS144, ASN170, VAL173,
GLU199, MET201 and VAL203 [11].
The grid region assigned for GRM 3 protein was 74, 108,
110, 165, 188, 186, 191, 233, 236, 238, 242, 260, 318, 323
and 409 [12].
The ligands (compounds of the plants V. wallichii, A.
calamus and A. racemosus) were converted to a single file.
Using LigPrep, energy minimization was done.
The Virtual Screening was carried out using the receptor
and ligand as mentioned above.
GRM3
MEHGTLLAQPGLWTRDTSWALLYFLCYILPQTAPQVLRIGGIFETVENEPVNVEELAFKFAVTSINRN
_consrvd
_aln.p
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
70
80
90
100
110
120
130
QFSTSEFRLTPHIDNLEVANSFAVTNAFCSQFSRGVYAIFGFYDKKSVNTITSFCGTLHVSFITPSFP
--------------------------------------------------------------------------------------------------------------------------------------RTLMPNTTLTYDIQRINLFDSFEASRRACDQLALGVAALFGPSHSSSVSAVQSICNALEVPHIQTRWK
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
140
150
160
170
180
190
200
TDG------THPFVIQMRPDLKGALLSLIEYYQWDKFAYLYDSDRGLSTLQAVLDSAAEKKWQVTAIN
--------------------------------------------------------------------------------------------------------------------------------------HPSVDNKDLFYINLYPDYAAISRAILDLVLYYNWKTVTVVYEDSTGLIRLQELIKAP-----SRYNIK
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
210
220
230
240
250
260
270
VGNINNDKKDETYRSLFQDLELKKERRVILDCERDKVNDIVDQVITIGKHVKGYHYIIANLGFTDGDL
--------------------------------------------------------------------------------------------------------------------------------------IKIRQLPSGNKDAKPLLKEMKKGKEFYVIFDCSHETAAEILKQILFMGMMTEYYHYFFTTLDLFALDL
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
280
290
300
310
320
330
340
LKIQFGGAEVSGFQIVDYDDSLVSKFIERWSTLEEKEYPGAHTATIKYTSALTYDAVQVMTEAFRNLR
--------------------------------------------------------------------------------------------------------------------------------------ELYRYSGVNMTGFRLLNIDNPHVSSIIEKWSMERLQAPPRPETGLLDGMMTTEAALMYDAVYMVAIAS
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
350
360
370
380
390
400
KQRIEISRRGNAGDCLANPAVPWGQGVEIERALKQVQVEGLSGNIKFDQ-NGKRINYTINIMELKTNG
--------------------------------------------------------------------------------------------------------------------------------------HRASQLTVSSLQCHR----HKPWRLGPRFMNLIKEARWDGLTGHITFNKTNGLRKDFDLDIISLKEEG
_aln.p 410
420
430
440
450
460
470
3KG2A
PRKIGYWSEVDKMVLTEDDTSGLEQKTVVVTT----------------------ILESPYVMMKANHA
3H6GA
------------------------THVLRFGGIFEYVES---------GPMGAEELAFRFAVNT---1YAEA
-----------------------SNRSLIVTT----------------------ILEEPYVLFKKSDK
GRM3
TEKAAGEVSKHLYKVWKKIGIWNSNSGLNMTDSNKDKSSNITDSLANRTLIVTTILEEPYVMYRKSDK
_consrvd
*
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
480
490
500
510
520
530
540
ALAGNERYEGYCVDLAAEIAKHCGFKYKLTIVGDGKYGARDADTKIWNGMVGELVY--GKADIAIAPL
----INRNR----TLLPN-------TTLTYDTQK----INLYDSFEA---SKKACDQLSLGVAAIFGP
PLYGNDRFEGYCIDLLRELSTILGFTYEIRLVEDGKYGAQDDVNGQWNGMVRELID--HKADLAVAPL
PLYGNDRFEGYCLDLLKELSNILGFIYDVKLVPDGKYGAQN-DKGEWNGMVKELID--HRADLAVAPL
*
*
*
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
550
560
570
580
590
600
610
TI---TLVREEVID--------------------FSKPFMSLGI--SIMIKKPQKSKPGVFSFLDPLA
SHSSSANAVQSICNALGVPHIQTRWKHQVSDNKDSFYVSLYPDFSSLS-------------------AI---TYVREKVID--------------------FSKPFMTLGI--SILYRK---------------TI---TYVREKVID---F-----------------SKPFMTLGI--SILYRKPNGTNPGVFSFLNPLS
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
620
630
640
650
660
670
680
YEIWMCIVFAYIGVSVVLFLVST------------N--------EFGIFNSLWFSLGAFMQPRS-----------------------------------------------------------------------------------------------------------------------------------------PDIWMYVLLACLGVSCVLFVIARFTPYEWYNPHPCNPDSDVVENNFTLLNSFWFGVGALMQQGSELMP
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
690
700
710
720
730
740
--LSGRIVGGVWWFFTLIIISSYTANLAAFLTVERMVSPIESAE----------DLSKQTEIAYGTLD
----------------------------------------RAILDLVQFFKWKTVTVVY-----------------------------------------------IDSAD----------DLAKQTKIEYGAVE
KALSTRIVGGIWWFFTLIIISSYTANLAAFLTVERMESPIDSAD----------DLAKQTKIEYGAVR
III.
Amino acid sequence of COMT and GRM3 were
retrieved from NCBI’s database.
Homology modelling of COMT was carried out using the
software Modeller9v8 with the templates 3BWMA, 2ZLBA
and 1JR4A (structure retrieved from RCSB’s pdb database)
and five models were generated.
Rampage Ramachandran Plot server was used to generate
the values of COMT protein obtained in favoured, allowed
and outlier region (Table I, Fig. 4).
As per Ramachandran Plot, either Model 2 or Model 5
was selected as the best protein since both are having same
and maximum number of the residues in favoured region
(also same number of residues in allowed region and outlier
region) (Fig. 5).
Homology modelling of GRM3 protein was carried out
using the software Modeller9v8. The templates used for
GRM3 mutation protein were 3KG2A, 3H6GA, 1YAEA and
five models (3D structures) of the GRM3 mutation protein
were generated. Rampage Ramachandran Plot server
generated the values of GRM3 protein obtained in favoured,
allowed and outlier region (Table 2, Fig. 6).
As per the Ramachandran Plot, Model 4 was selected as
the best protein since it is having least residues in the outlier
region (Fig. 7):
The COMT protein (model #2 or 5) was virtually
screened with the compounds of V. wallichii. Glide XP
visualizer showed COMT’ LYS144 interacting with
baldrinal from V. wallichii. The glide score was -6.09 (Fig.
8).
COMT protein (model #2 or 5) was screened with the
compounds of A. calamus. Glide XP visualizer showed
COMT’ LYS144 interacts with calamusenone from A.
calamus. The glide score was -5.23 (Fig. 9).
_aln.p 750
760
770
780
790
800
810
3KG2A
SGSTKEFFRRSKIAVFD--------------KMWTYMRSAEPS-------------------VFVRT3H6GA
-------DDSTGLIRLQELIKAPSRYNLRLKIR--QLPADTKDAKPLLKEMKRGKEFHVIFDCSHEMA
1YAEA
DGATMTFFKKSKISTYD--------------KMWAFMSSRRQS-------------------VLVKSGRM3
DGSTMTFFKKSKISTYE--------------KMWAFMSSRQQT-------------------ALVR-_consrvd
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
820
830
840
850
860
870
880
----------------------TAEGVARVRKSK-----GKYAYLLESTMNEYIEQR----------AGILKQALAMGMMTEYYHYIFTTLDLFALDVEPYRYSGVNMTGF------RILNTENTQVSSIIEKWS
----------------------NEEGIQRVLTS-------DYAFLMESTTIEFVTQR------------N-------------------SDEGIQRVLTT-------DYALLMESTSIEYVTQRNCNLTQIGGL-
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
890
900
910
920
930
940
950
-----------------------------------------------KPCDTMKVGGNLDSKGYGIAT
MEKPDSGLLDGFMTTDAALMYDAVHVVSVAVQQFPQMTVSSLQCNRH-------------------------------------------------------------------N-CNLTQIGGLIDSKGYGVGT
-----------------IDSKGYGVGTPIGSPYRDKITIAILQLQEEGKLHMMKEKWWRGNGCPEEDN
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
960
970
980
990
1000
1010
1020
PKGSSLGTPVNLAVLKLSEQGLLDKLKNKWWYDKGECGA-------------------------KDSG
-KPWRFGTRFMSLIKEAH--------WEGLTGR------ITFNKTNGLRTDFDLDVISLKEEGLEKIG
PMGSPYRDKITIAILQLQEEGKLHMMKEKWWRG---NGC----------------------------KEASALGVENIGGIFIVLAAGLVLSVFVAIGEFIYKSRKNNDIEQAFCFFYGLQCKQTHPTNSTSGTT
_aln.pos
3KG2A
3H6GA
1YAEA
GRM3
_consrvd
1030
1040
1050
1060
S-------KEKTSALSLSNVAGVFYILVGGLGLAMLVALIEFCYK
TWDPASGLNMTE----------------------------------------------------------------------------LSTDLECGKLIREERGIRKQSSVHTV-------------------
RESULTS & DISCUSSION
Based on this data, the 3D structure of GRM3 protein
was generated by modeler.
17
COMT protein (model #2 or 5) was virtually screened
with the compounds of A. racemosus. Glide XP visualizer
showed COMT’ GLU90 interacting with racemosol from A.
racemosus. The glide score obtained was –6.25 (Fig. 10).
The GRM3 protein (model #4) was virtually screened
with the compounds of V. wallichii. Glide XP visualize
showed GRM3’s LYS59 interacting with homobaldrine of V.
wallichii. The glide score was -6.59 (Fig. 11).
The GRM3 protein (model #4) was virtually screened
with the compounds of Acorus calamus. Glide XP visualize
showed GRM3’ TYR154 & ASP230 interacting with
galangin from Acorus calamus. The glide score was -7.77
(Fig. 12).
The GRM3 protein (model #4) was virtually screened
with the compounds of A.racemosus. Glide XP visualizer
showed GRM3’s THR133 & ASP230 interacting with
racemosol from A. racemosus. The glide score obtained was
-8.37 (Fig. 13).
IV.
[11] Lee JY and Kim Y, “Comparative Homology Modeling and Ligand
Docking Study of Human Catechol-O_Methyltransferase for
Antiparkinson Drug Design,” Bull. Korean Chem. Soc. (2005)
26(11):1695-1700.
[12] Tsuchiya D, Kunishima N, Kamiya N, Jingami H and Morikawa K,
“Structural views of the ligand-binding cores of a metabotropic
glutamate receptor complexed with an antagonist and both glutamate
and Gd3+,” PNAS (2002) 99(5):2660-2665.
TABLE I.
VALUES OF COMT PROTEIN OBTAINED IN FAVOURED,
ALLOWED AND OUTLIER REGION USING RAMPAGE RAMACHANDRAN PLOT
SERVER
Number of
residues
in
favoured
region
(~98.0%
expected)
213
(97.3%)
Number of
residues
in
allowed
region
(~2.0%
expected)
5 (2.3%)
Number
of
residues
in
outlier
region
Model 2
215
(98.2%)
3 (1.4%)
1 (0.5%)
Model 3
213
(97.3%)
5 (2.3%)
1 (0.5%)
Model 4
212
(96.8%)
6 (2.7%)
1 (0.5%)
Model 5
215
(98.2%)
3 (1.4%)
1 (0.5%)
Model 1
CONCLUSION
COMP protein showed good interaction with baldrinal
from Valeriana wallichii, calamusenone from Acorus
calamus and racemosol from Asparagus racemosus.
GRM3 protein showed good interaction with
homobaldrinal from Valeriana wallichii, galangin from
Acorus calamus and racemosol from Asparagus racemosus.
These
compounds,
baldrinal,
calamusenone,
homobaldrine, galangin and racemosol, could be tested invitro and in-vivo for their efficacy in treating the disorder.
Selected
1 (0.5%)
selected
selected
REFERENCES
TABLE II.
VALUES OF COMT PROTEIN OBTAINED IN FAVOURED,
ALLOWED AND OUTLIER REGION USING RAMPAGE RAMACHANDRAN PLOT
SERVER.
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1–15.
Model 1
Model 2
Number of
residues
in
favoured
region
(~98.0%
expected)
807
(88.1%)
820
Number of
residues
in
allowed
region
(~2.0%
expected)
65 (7.1%)
61 (6.7%)
(89.5%)
Model 3
Model 4
Model 5
820
(89.5%)
54 (5.9%)
822
(89.9%)
58 (6.3%)
821
57 (6.2%)
(89.8%)
18
Number
of
residues
in
outlier
region
Selected
44
(4.8%)
35
(3.8%)
42
(4.6%)
34
(3.7%)
36(3.9%)
selected
acetoxy valerenic acid
bornyl_acetate
β-sitosterol
isovaltrate
acevaltrate
bornyl isovalerate
calarene
valeranone
baldrinal
2,3-dihydro-4,5,7-trimethoxy-1- ethyl-2-methyl-3-(2,4,5-trimethoxy
phenyl)indene
fenchene
homobaldrinal
2,4,5-trimethoxy benzaldehyde
2,6-diepishyobunone
valerenal
3β, 22α, 24, 29-tetrahydroxyolean-12-en-3-O-{-β-D-arabinosyl(1→3)}-βD-arabinopyranoside
valerenic acid
valtroxal
valepotriate
valtrate
xanthorrhizol
4, 5, 8-trimethoxyxanthone-2-O-β-D-glucopyranosyl(1→2)-O-β-Dgalactopyranoside
Figure 1. Active constituents of Valeriana wallichii
acoradin
1α, 2β, 3γ, 19α-tetrahydroxyurs-12en-28-oicacid-28-O{-β-Dglucopyranosyl (1→2)} β- D- galactopyranoside
acoragermacrone
Acoramone(1,2,4 –trimethoxy-5(2-propanoyl) benzene
19
β-sitosterol
Calamusenone
asparagamine
racemosol
cis-asarone(cis-1,2,4 –trimethoxy-5(2- propenyl)benzene
sarsasapogenin
Galangin
isoeugenol methyl ether
γ-cis-asarone(cis-1,2,4 –trimethoxy-5(2propenyl)benzene
Isocalamendiol
Limonene
shatavarin
Figure 3. Active constituents of Asparagus racemosus
Preisocalamendiol
Shyobunone
Thujane
Z-3-(2,4,5-trimethoxy phenyl)-2-propenal
Figure 4. Ramachandran plot of COMT protein model #2 or 5.
Figure 2. Active constituents of Acorus calamus
20
Figure 5. COMT protein model #2 or 5 (visualization in SPDBV)
Figure 9. Interaction of COMT protein with calamusenone from Acorus
calamus
Figure 6. Ramachandran Plot of Grm3 mutation protein model #4
Figure 10. Interaction of COMT protein with racemosol from Asparagus
racemosus
Figure 7. GRM3 protein model #4(visualization if SPDBV)
Figure 11. Interaction of GRM3 protein with homobaldrine from Valeriana
wallichii
Figure 8. Interaction of COMT protein with baldrinal from Valeriana
wallichii
21
Figure 12. Interaction of GRM3 protein with galangin from Acorus
calamus
Figure 13. Interaction of GRM3 protein with racemosol from Asparagus
racemosus
22