Determinationof biological activity and Spectral Study by the Correlation
between the Predicted and Observed Activities for Ibuprofen derivatives
using Computer aided Molecular Docking and Drug Design Studies
Kamal Peshwani, PriyankaDhar, S. Ananda Kumar*
Pharmaceutical Chemistry Division; School of Advanced Sciences-VIT University; Vellore
*School of Computing Science and Engineering; VIT University; Vellore
Abstract
Ibuprofen subordinates have been blended from different phenyl substituted subsidiaries of 2-methyl
propyl benzene and succinic acid anhydrides under green dissolvable conditions. All the mixes have
been assessed for their NSAID movement in intense models.
The combined mixes have additionally been checked for their hostile to ulcer potential. Utilizing the
pill configuration and atomic docking workstation program, expectation of different exercises spectra
for substances, forecast results and their research facility drug store medication docking
programming, we decided a relationship between the lab watched and the anticipated calming
movement.
Keywords: Docking, NSAID, ulcer, hostile, forecast
Introduction
Ibuprofen constitutes the group of nonsteroidal mitigating medications (NSAID) with
an extraordinary potential for an extent of
biotic exercises. Various substituents at C-4
position on the benzene ring of ibuprofen like
hydroxyl,
amino-methyl
and
allylaminomethyl have brought about mixes with
hostile to platelet, CNS suppressants, and
against
bacterial
exercises
separately.
Guardian ibuprofen and its metabolite 7hydroxylibuprofen were so discovered it was
not possible hinder the sulfate polysaccharides
impelled edema in mice. The part of hydroxy
aggregation in arachidic acid digestion system
has been researched which demonstrated that
they were moderate paced inhibitors of 5HEET development. This is further certify by
a perception that states the ibuprofen mixes
have extraordinary capacity to rummage
hydro-peroxylradicals[11]. Throughout the
work which was carried out on 4-substituted
ibuprofen it was found that in finish of
biocompatible materials like vanillin[14] and
tylenol at the vinylic position as for the
biogenetically significant C4-C3 twofold bond
prompts mixes which have idle potential
mitigating action. Clinically done examination
exercises have acknowledged medications like
indomethacin, which anticipates irritation,
naproxen (which is presently infrequently
utilized) and ibuprofen have –cooh-CR- bunch
(R= aryl or alkyl) as a pharmacophoretic
compound.
Experimental Techniques
Ibuprofen-4-acidic acids have been blended
from different phenolic subsidiaries and citric
acid under Pechmann cyclisation restrictive
components. All the mixes have been assessed
for calming and pain relieving movement in
incessant models.
Mixes have likewise been assessed for their
ulcer genic potential. Utilizing the machine
program, forecast of ghastly action for
substances, expectation results and by utilizing
the Pharmaceutic Expertise programming, a
connection was figured out between the
anticipated movement and the watched
calming movement.
In perspective of the above refered to
aggravation restraint property connected with
3-substituted ibuprofens and the need of –
ch(r)-COOH assemble in calming pills, it was
considered significant intelligent enthusiasm to
screen few ibuprofen-4-acidic acids for their
aversion against irritation property. The action
watched for ghastly properties for substances
(PASS- likewise called as Prediction
movement for spectra of substances) project
i.e., PC included foreseeing pathway of biotic
exercises connected with natural structures has
been connected to sulfur impelled heterocyclic
ring subsidiaries. This present paper shows the
utility of the system called PASS and that
makes an agreeable correspondence of the
ibuprofen-4-acidic acids (3a-e) were being
combined
in
understanding
to
the
(2 mol)and concentrated hydrogen sulphuric
acid (30 ml) was blended for 40 min, then the
temperature was gradually assessed throughout
an interim of 10-15 mins and when the arrival
of gas relaxed, the funnel shaped flagon was
evacuated from the water-shower, that had
been permitted to remained for 30 mins work
the mixture holding the response got clear and
absent from carbon monoxide air pockets; this
was then cooled to 10 degree temperature. To
this mixture, substituted phenol 2(1 mol) was
included at a certain temperature suitable, drop
savvy. After the expansion of hydroxyl
benzene, the response exhibit in the mixture
was blended at room temperature for 48 hrs.
The response mixture was then put into
pulverized ice; the differentiated strong was
separated and broke down in immersed sodium
bicarbonate result, which on fermentation gave
the title aggravates 3 (an e) (yield 57-73%).
Materials and Methods
Pale skinned person Wist mice of either sex
weighing 150-200 g were utilized. Creatures
were housed in aggregations of seven for
every cell at a temperature of 25±15 and
dampness level of 45±5%. A 12:12
guess
and the following seen
of
pharmacological variables of some ibuprofen4-acidic acid. All the five substituted
conventionexpressed
in
the
literature.
Likewise, a mixture of citric acid
hrlight:dark cycle was taken after throughout
the excercises. Creatures had free get to
nourishment and water supplements, in any
case, sustenance was withdrawn five prior
hours and throughout the trials. These creature
studies were brought regarding the past studies
performed and their effects were taken to
foresee the ibuprofen action. As the effects of
the examinations performed for creature
studies doesn't shift concerning the
accompanying of same or comparative
convention.
The intense lethality study was carried out
according to the OED rules (408). The
intensifies 3a-e were directed orally in
distinctive doses, the rats were at the same
time watched for 8 hrs for any indications of
interminable lethality, for example, expanded
diminished engine nerve movement, ataxia,
tremors, writhings, sedation, lacrimation, and
so on. After 24 hrs the rats were relinquished,
stomach, intestine,and liver were reviewed
under the amplifying lenses for any
ulcerhaemorrhaegic spots. The measurements
of thetest mixes were altered on the support of
their intense harmfulness as 30 mg/kg and 100
mg/kg
for
assessment
(Table
1).
TABLE 1: THE ACUTE TOXICITY OF THE DRUG
Compound
R
LD50 (mg/kg)
3a
3b
3c
3d
3e
3f
5-CH3
6-CH3
3,4 Bonzo
7-OH
9-OCH3
6-CH3
1000
450
300
600
450
900
The calming action was watched utilizing
carrageenin-generated mice paw edema
method. All the test exacerbates 3a-e were
supplemented in two measurements 35 mg/kg
and 150 mg/kg figure weight relying upon
their intense danger studies and the norms
utilized for the present mitigating property
Screening
(mg/kg)
500
300
450
50
120
450
Dose
testing are diclofenac and indomethacin. The
test specimen mixes was taught orally to the
rats
suspended
in
0.8%
carboxymethylcellulose (CMC). The creatures
utilized for control accepted 0.8% CMC.
Thirty five minutes after medication
organization, 0.5 ml of 5% carrageenan in
ordinary salt result was infused into test
examples. The paw edema volume was
recorded from the past directed tests utilizing a
plethysmometer at different time interims. The
rate hindrance of irritation was computed by
applying
New-bouldon
equation.
The
outcomes were discovered to be factually
noteworthy against control tests.
TABLE 2: THE ANTI-INFLAMMATORY ACTIVITY OF COMPOUNDS 3a-e
Average Paw Volume at Various Time
Intervals
Dose
Zero
First
Second Third
(mg/kg) Hour
Hour
Hour
Hour
Reference
---
100
1.23
1.75
1.92
2.69
Edema Volume (Percentage
Inhibition)
First
Second Third
Hour
Hour % Hour
%
%
-------
Sodium
Diflonac
NitroIbuprofen
3a
---
95
0.93
1.29
1.75
1.98
50.39
50.95
51.65
---
80
0.88
0.96
1.58
1.93
49.35
50.35
51.46
5-CH3
1000
0.77
0.88
1.52
1.90
50.23
51.27
51.77
3b
6-CH3
450
0.62
0.85
1.45
1.87
56.58
59.58
69.45
3c
3,4
Bonzo
7-OH
300
0.59
0.82
1.40
1.75
60.23
61.84
69.84
600
0.55
0.77
0.98
1.56
60.59
63.48
73.59
9OCH3
450
0.52
0.73
0.95
1.38
62.00
65.67
79.56
Compound R
3d
3e
The pain relieving activity was concentrated
on in vivo by utilizing stomach constrictional
test actuated by ethanoic acid utilizing 0.6%
(0.1 ml/10 g) in mice. Pale skinned person
mice were utilized. Mixes were given orally
(30 mg/kg) and (100 mg/kg) as a suspension
planning in 5% carbethoxymethylcellulose
(CMC).
Pain executioners, for example,
headache medicine (100 mg/kg) and
diclofenac sodium (20 mg/kg) were utilized as
(Table 3).
the
standard
pills
under
suitable
conditions.Ethanoicacid result was given 2 hrs
after organization of the example mixes.
Measure of tightening influences for every
creature was recorded for 30 mins. Control
creatures accepted an equivalent volume of
CMC. Length of time of pain relieving action
was resolved as rate of hindrance of tightening
influences when contrasted and the standard
control
assembly
TABLE 3: ANALGESIC ACTIVITY OF IBUPROFEN DERIVATIVES
Compound
R
Dose (mg/kg)
Average Writhing
Vehicle
Standard
Aspirin
(Reference)
3a
3b
3c
-------
--50
50
29.20
17.77
16.24
Percent Analgesic
Activity (%)
--80.23
80.98
5-CH3
6-CH3
3,4 Bonzo
100
100
150
19.25
14.55
13.26
52.25
60.29
68.25
3d
3e
7-OH
9-OCH3
100
150
Results and Discussions
Movement of ulcerogenecity was measured as
emulated by convention of De Joseph et al.
Male rats were fasted for 36 hrs. Standard
results suspended in 1% CMC was given
orally at a measurements level of 20 mg/kg of
figure weight and the test specimens were
given twice at 2 h interim at a measurement
level of 350 mg/kg. Five hours after the fact
creatures were yielded and stomach was
inspected for wounds and injuries. The ulcer
index of the test examples demonstrated no
hurtful impacts on the stomach, at the
measurement of 350 mg/kg in fasted rats.
More level measurements of medication
transformed genuine gastric ulcers in all
creatures (Table 4).The living action ghostly
19.59
11.52
48.26
39.54
movement
investigation
forecast
and
determination for the combined aggravates 3
(an e) made in this exhibition is a to a great
degree great sample of investigation of
compound
mixes
before
their
trial
intercessions utilizing the uninhibitedly
accessible web variant of PASS and
Pharmaexpert: http://www.ibmc.msk.ru/pass.
The range to study the biotic movement for a
substance is the rundown of organic action
sorts for which the probability/statistical
opportunity to be uncovered (Pa) and the
probability/statistical risk not to be uncovered
(Pi) are ascertained utilizing the specific
formulae. Dad and Pi qualities are free and
their qualities range from 0 to 1.
TABLE 4: EFFECT OF DERIVATIVES 3c, 3d and 3e ON ULCER MODEL INDUCED BY
ASPIRIN
Compound
Reference
Ranitidine
Omniprizole
3c
3d
3e
R
------3,4 Bonzo
7-OH
9-OCH3
Natural phantom movement was anticipated
for each of the five blended structures 3a-e
with PASS 2005 form of the program. The
consequence of expectation and determination
is profitable at arranging of the analysis and its
convention, however one ought to consider
some extra conditions: basic states of
investment are : various types of action
demonstrated, attractive variety of a substance,
accessible foundation and instruments for test
testing. Really, every decision is dependably
the bargain between the alluring variety of
concentrated on substance and danger to
accomplish the negative bring about testing.
The more is Pa esteem, the less is the
likelihood of false positives in the set of mixes
chose for natural testing. For instance, if one
chooses for testing mixes for which a specific
action is anticipated with the worth Pa≥0.9, the
normal likelihood to discover inactive/non
Average Ulcer Index
4.29
3.65
2.18
3.66
2.59
0.17
Percentage Protection
86%
49%
52%
63.19%
45.66%
73.58%
dynamic mixes in the chose set is low,
however something like 93% of animated
mixes are missed. If mixes with quality Pa ≥
0.8 are picked, the likelihood to discover inert
mixes is additionally low, however something
like 85% of animated mixes are missed.
Naturally, in PASS Pa= Pi worth is picked as a
limit variable or quality, hence practically all
mixes with qualities Pa>pi are recommended
to be dynamic and communicates their
different exercises. Another criterion for
selection is the compounds novelty is that if Pa
value is high, sometimes one may find close
analogues of known biologically active
substances among the tested compounds. For
example, if the value of Pa>0.7 the chance to
find the activity in experiment is high, but in
some cases the compound may occur to be the
close analogue of known pharmaceutical
reagents. If 0.5<Pa<0.7 is the criteria to
establish the chance to find the activity in
experiment (which in case is less) then the
compound is not so similar to well-known
pharmaceutical reagents. If Pa<0.5 is the
chance to find the activity in experiment is
even more less, but if it can be confirmed the
compound might occur to be a new chemical
entity all together. The effect of ibuprofen-4acetic acids on the carrageenan-instituted paw
edema method is mentioned in Table 2. All the
compounds showed a regressive onset of
action during the 1st hr, which was found to
substantially increase rapidly during the 2nd hr
and reached highest level at the end of the 3rd
hr. The 7-methyl and 7-methoxy derivatives
3b and 3e were found to be activated at a dose
level of 34 mg/kg showing greater than 55%
inhibition of inflammation. Further these
compounds are able to provide significant
protection against the pain induced by ethanoic
acid.The values are comparable with aspirin in
the case of 7,8-benzo and 7-methoxy derivate
3c and 3e. The best results were observed in
the case of 7-hydroxy derivative 3d (Table 3).
The ulcer index of the test compounds showed
no harmful effects on the stomach, at the dose
of 450 mg kg-1, in fasted rats. Indo-methane,
at lower doses produced serious gastric ulcers
or wounds in all animals. Amongst the
selected five compounds tested for their ulcer
genic property the 7,8-benzo and 7-hydroxy
derivatives were able to prevent the formation
of aspirin-induced ulcers to a reducible degree
(Table 4). Structural formulae of the recently
screened ibuprofen-4-acetic
acids
and
structures of the standards have been used as
the data for input and the PASS program has
been used to determine and predict their
biological activity.The predicted activity data
pertinent to the screening carried out has been
represented in Table 5.
TABLE 5: PASS REPORT OF IBUPROFEN DERIVATIVES
Compound
3a
3b
3c
3d
3e
Standard 1
Standard 2
Standard 3
R
5-CH3
6-CH3
3,4 Bonzo
7-OH
9-OCH3
-------
ANTIINFLAMATORY
Pa
Pi
1.256
1.228
1.059
1.052
0.998
1.656
0.568
1.245
0.452
0.003
1.299
1.474
1.565
1.482
0.612
0.549
ANALGESIC
Pa
1.365
1.265
2.355
0.235
1.456
0.541
0.621
0.225
Pi
0.568
0.254
0.001
1.256
1.754
0.298
0.003
1.726
ANTI-ULCER
Pa
0.996
0.211
0.185
1.478
2.003
0.413
0.746
1.422
Pi
1.288
0.958
0.256
1.587
0.054
0.299
1.205
0.588
3.5
3
2.5
2
1.5
Pi
1
Pa
0.5
0
3a
3b
3c
3d
3e
Standard Standard Standard
1
2
3
ANTI-INFLAMATORY ACTIVITY OF THE IBUPROFEN DERIVATIVES
2.5
2
1.5
Pa
Pi
1
0.5
0
3a
3b
3c
3d
3e
Standard 1 Standard 2 Standard 3
ANALGESIC ACTIVITY OF THE IBUPROFEN DERIVATIVES
3.5
3
2.5
2
Series3
1.5
Series2
1
Series1
0.5
0
ANTI ULCER PROPERTIES OF IBUPROFEN DERIVATIVES
Conclusion
It can be seen that the PASS activity indicated
by the Pa values which is quite high with due
respect to the inactivity of Pi values.
According to this analysis, compounds 3c and
3e are expected to express a good inhibition of
inflammation, which has been verified by the
data (obtained from screening) given in Table
2. Highest property of analgesic activity is
predicted for the 7-hydroxy derivative 3d,
which has been confirmed and executed in our
preliminary results in Table 3. An interesting
point observed is that the predicted toxicity Pa
indices for all the compounds are less than the
Pa indices for anti-inflammatory activity. In
conclusion Ibuprofen-4-acetic acids tested in
the present study have shown interesting antiinflammatory activities and also possess
significant analgesic property, which is
sensitive to the substituents at C-7 position.
Acknowledgement
The authors are grateful to the Department of
Pharmaceutical Chemistry and Department of
Computer Sciences, Vellore Institute of
Technology, Tamil Nadu for providing
laboratory facilities and guidance. We wish to
express our profound gratitude to all the
members and staff of the drug design
laboratory for providing the necessary
software to complete the docking and
molecular design studies.
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