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2
the
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International Journal of Medicinal
International
small intestine, Journal where
of Medicinal Chemistry
it absorbs dietary glucose and Chemistry
Volume 2014, Article ID 739646, 15 pages
galactose
http://dx.doi.org/10.1155/2014/739646 relationships between structural modifcations and
from the gut lumen [13]. SGLT2, expressed exclusively activities
in against hSGLT2 inhibitors with the help of QSAR
the kidney, is located in the S1 segment of the proximal modeling.
convoluted tubule of the kidney. It is a low-afnity, high- 2.2. Computational Details. All the computational
capacity cotransporter and is responsible for 90% of studies
renal were performed by V-life MDS (Molecular Design Suite)
Research Article
glucose reabsorption [14]. Several therapeutic agents 3.5
are software supplied by V-life Sciences Technologies Pvt.
Molecular Modeling Studies of Thiophenyl C-Aryl Glucoside
available for monotherapy or for combination therapy Ltd.,
SGLT2 Inhibitors as Potential Antidiabetic Agents
with
different mechanisms to treat diabetics, such as
Pune, India [69]. The sketched structures were used for
the
metformin, calculation of 2D molecular descriptors using QSAR
rosiglitazone, sitagliptin, acarbose, and glimepiride [15]. module
The obvious need for new approaches to treat patients of Molecular Design Suite software. Each compound was
with 1 2 subjected to energy minimization and batch
uncontrolledMukesh T2DM C.has Sharma
prompted andcontinuous
Smita Sharma optimization
exploration 1
School of Pharmacy, Devi Ahilya University, Takshila Campus, using Merck
Khandwa Molecular
Road, IndoreForce452 Field (MMFF), fxing Root
of alternative
001, Indiatargets involved in maintenance of ˚
glucose 2 Mean Square Gradients (RMS) to 0.01 kcal/mol A [70].
homeostasis. Department
Several of Chemistry,
SGLT2 Chodhary Dilip Singh Kanya Mahavidyalya,
The sphere Bhind 477001,
exclusion India [71] was adopted total
method
Correspondence shouldinhibitors
be addressed have to been
Mukesh C. Sharma;
reportedmukesh2206@rediffmail.com
as set
undergoing clinical
Received 14 Maytrials. Phlorizin
2014; Revised [16], 3-
29 October of inhibitors
2014; Accepted 29 October was2014;
divided randomly
Published 10 into a training set
December 2014
(benzo[b]furan- (26
5-yl)-2 ,6 Academic Editor: Maria
-dihydroxy-4 Cristina Breschi
-methylpropiophenone-2 -O -�- compounds) for generation of QSAR models and a test
D- set
2.3. Calculating 2D Descriptors. In the current approach,
Copyright [17], © 2014 M. C. Sharma and S. Sharma. This isan
ancompounds)
(7 open access hasarticle
for distributed
validation under the Creative
glucopyranoside
Commons Attribution
sergliflozin [18], and remogliflozin attempt
(1) the maximum been taken
value to ofof the developed
understand
pIC model.
the structural
50 of test set should be
[19] are O-glycosides and show strong inhibition of Thisless
and physicochemical requirements of a set of hSGLT2
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
SGLT2. properly cited. random
inhibitors division
byorthe of
helpdata set
toofmaximum will bevalue
regression done ofthrough
2D quantitative ofseveral
A QSAR study on thiophenyl derivatives as SGLT2 inhibitors cycles asthan
potential
in order
equal
antidiabetic
to get the agents
best QSARwas model. pIC50with
performed This study
They also demonstrate efcacy in vivo when structure-
training
thirty-three
administered will
activity
(2) relationship
the minimum (2D
value QSAR).
of pICThe ofenergy-minimized
test set should be
compounds. Comparison of the obtained results indicated the set, 50
superiority of the genetic algorithm over the simulated
orally inannealing
rats or mice. They induce a glucosuric help inhigher
geometry rational
was drug
used
than designing
or for
equaltheto of theseof
calculation
minimum derivatives
the various
value as2D
of pIC50 of
One of the
response, andmainstepwisefeatures of diabetesvariable
forward-backward is the elevation
method for SGLT2
offeature
descriptors
training
selection.such
set.as
The topological,
best 2D QSAR model shape and geometrical,
showed satisfactory
blood
the result of the blockade of renal glucose reabsorption, inhibitors
statistical and for the eradication of T2DM. The unicolumn
sugar with
and its deleterious
parameters for the dataconsequences in a �variety
set (�2 = 0.8499, statistics
of and
2 = 0.8267, pred �2 of
physicochemical the training
= 0.7729) parameters anddescriptors
with four test
suchsets are reported
as individual
describing (H- in
the
tissues nature lead
consequently of to reduction of the blood glucose Table 2.
Acceptor
[1]. Thus,
level substituent
control of groups and the glucose
the plasma environmentlevelofisthe of substitution
The
count,site.
that maximum Evaluation
induces
H-Donor and of
hyperglycemia
count, the
minimum model
XlogP, implied
value
[6].
retentionin that
Medical electron-rich
training
index and test
complications
(Chi),
substitution set
utmost
and improvement of insulin sensitivity [20]. Quantitative element associated with T2DM include cardiovascular disease,
position improves the inhibitory activity. The good predictive 3D-QSAR models by k-nearest neighbor (kNN) method
importance
structure-activity in therelationship
for molecular treatment of(QSAR) this disease.
studiesIncan recent
be were
stroke,
count, compared in a wayestate
estate numbers, that contribution, and
years, to
utilized feld predict
analysis eye irritation
(MFA) potential as an
have cross-validated nephropathy,
alignment-
coefcient �2 value of 0.7663 and retinopathy,
predicted �renal
2 value failure, andThe results
of 0.7386.
the ideahave
alternative thatshowed
affecting glucose absorption in the amputations of
independent descriptors were used as predictor
intestine
in
1. silico method,
that
Introduction just as
thiophenyl it has
groups arebeen used successfully
necessary for activity and tohalogen,
the extremities
variables),bulky,asand[7].
lessInbulky
recent years,
groups much attention
in thiophenyl nucleus has
and/or the
predict enhanced
severalglucose thereabsorption
other toxicological in endpoints
the kidneyfor might
some be they
been were found to be appropriate for the development
a
time biological
[21]. Hence,activity. These studies
in continuation are efforts
to our promising for the development
[22–67] of novel SGLT2 inhibitor,
given to sodium-dependent
of glucose which may have potent
cotransporters
possible
in
2.1. Data antidiabetic
way
Set.to Thecontrol
biological
the sugar
data level
set washaschosen
evolved. from a models.
(SGLTs), A considerable number of the 265
activity.
Diabetes QSAR studies for angiotensin II AT1 receptor, physicochemical
developing
series mediators of reabsorption of glucose in the human body.
comprises
antitubercular
of thirty-three a group
thiophenyl
agents, of metabolic
antimalarial
derivatives
disorders
activity,
as SGLT2characterised
inhibitors parameters,
Sodium-dependent 300 alignment
glucose cotransporter
type parameters, 2 (SGLT2)
and 99is a
by
antimicrobial
as high-capacity, low-afnity transporter expressed
atoms
2. Materials
chronic
activity,
potential and Methods
hyperglycaemia
antibacterial
antidiabetic activity,
agents
with reported
disorders
COX inhibitors,
by
in Lee
the et and al.so[68]. types
selectively
count descriptors calculations were done using
metabolism
forth.
The in the S1 domain of the proximal tubule in the kidney
the
of carbohydrate,
biological
In this study,
activitywe fat,
values
have
and [IC protein
taken
50 (nM)]
thiophenyl
thatreported
resultderivatives
inindefects in V-life,
and is MDSresponsible
3.5. Thefor preprocessing
90% of renal of glucose
the independent
reuptake.
secretion and action of insulin [2]. Dysfunction and
for
nanomolar Sodium dependent
variables (i.e., 2D descriptors)
glucose cotransporter
was done by 1 (SGLT1),
removingon
failurewere converted
performing
units 2D and 3Dtoquantitative
their molar structural-activity
units pIC50 and the other hand, is a low-capacity, high-afnity
of various organs, especially the eyes, kidneys, nerves, invariable
rela-
subse- transporter(constant column) which resulted in a total of
and
tionship
quently used
analysis as theanddependent
calculations variable
in order fortotheunderstand
QSAR distributed
216 molecular in the
descriptors
kidney, gut, to be andusedotherfortissues,
QSAR analysis.
heart,stereoelectronic
their
analysis. and the blood vessels properties.are the
Genetic
usualalgorithm
complications The responsible
various alignment-independent descriptors were
of converted to pIC50 for the QSAR analysis along with also
(GA),
The for the remaining 10% of glucose reuptake [8]. Na+
diabetes [3,
simulated
the annealing
4]. Diabetes (SA),isand mainly
stepwise
divided forward-
into four -glucose
calculated. In this study to calculate AI descriptors, we
main
backward
structure of the compounds in the series are listed in cotransporter (SGLT) is a membrane protein that plays
have
types 1including
variable
Table selection insulin-dependent
methods have been diabetes
employedmellitus for an important
used the following
role inattributes:
the reabsorption
2 (double of bonded
glucose atom),
in the 3
(type 1), with asterisk). The test compounds were
selec-
(marked kidneys.
(triple bonded
Sodium-dependent
atom), C, N, O,glucose S, H, F,cotransporters
Cl, Br, and I, and
non-insulin-dependent
tion
selected
of relevant descriptors. diabetesThe mellitus
obtained(type results 2), (SGLTs),
the distance range of 0–7. The QSAR models were built
gestational
provide
manually such that the structural diversity and wide mediators of reabsorption of glucose in the kidney, have
with
diabetes,
further
range insight
and other
into somespecifc benefcial
types [5].information
Diabetes in mellitus therecently
consideration
emerged of asthenovelapplicability
drug targets of the
for the
descriptor
type
structural
of activity in the data set were included. In this paper, a for treatment
the of
2 (T2DM)
modifcations
series of thiophenyl
accounts
to design for
compounds
almost
new potential
90%withof substitutions
diabetes
SGLT2 inhibitors.
cases,at X activity.
diabetesVarious
[9]. SGLT types
is known
of physicochemical
to have three descriptors
isoforms
with R
Moreover,
and new compounds with high predictive (SGLT1,
have
the property
activities
position of thiophenyl
of insulin moiety
resistance are and
subjected
beta-cell to SGLT2,
been calculated
and SGLT3) which
[10–12].
are shown
SGLT1inisthe expressed
data sheet
dysfunction
were
examining
designed. the primarily
(Table 3).
International Journal of Medicinal 3
Chemistry
S R
O
HO
HO
OH
OH
1 Cl 86.5 7.0629
OEt
2 Cl 34.6 7.4609
OH
3∗ Cl 140 6.8538
4 Cl 65.0 7.1870
5 Cl 54.6 7.2628
6∗ Cl 111 6.9546
7 Cl 94 7.0268
O
O
8 Cl 115 6.9393
4 International Journal of Medicinal
Chemistry
Table 1: Continued.
X
S R
O
HO
HO
OH
OH
9 Cl 70.7 7.1505
SMe
SEt
11 Cl 48.4 7.3151
12 Cl 11.9 7.9244
13 Cl 57.2 7.2426
O O
15 Cl 60.2 7.2204
16 Cl 4.47 8.3496
International Journal of Medicinal 5
Chemistry
Table 1: Continued.
X
S R
O
HO
HO
OH
OH
17 Cl 10.3 7.9871
18 Cl F 91.3 7.0395
S
OMe
OEt
20 H 8.73 8.0589
OH
21 H 50.2 7.2992
23 H F 21.1 7.6757
S
OEt
24 H 71.4 7.1463
6 International Journal of Medicinal
Chemistry
Table 1: Continued.
X
S R
O
HO
HO
OH
OH
Cl
26 H 451 6.3458
t-Bu
27 H 88.3 7.0540
28 H 69.6 7.1573
30 H 59.8 7.2232
31 Br 12.4 7.9065
S R
O
HO
HO
OH
OH
6.5
6
6 8
Observed activities
(d) (e)
8.5
Predict
ed 8 y = 0.874x − 0.082
activiti
7.5
es
7
6.5
6
6 8
Observed activities
(f) (g)
8.5
Predict
ed 8
y = 0.912x + 0.144
activiti
7.5
es
7
6.5
6
6 8
Observed activities
(h) (i)
8.5
Predict
ed 8
y = 0.801x + 1.483
activiti
7.5
es
7
6.5
6
6 8
Observed activities
Training set
Test set
(j)
Figure 1: (a) Thiophenyl ring (template structure). (b) Alignment of thiophenyl derivatives. (c) Contribution charts of the
descriptors for
the 2D QSAR model-1. (d) Plot of observed versus predicted activity by 2D QSAR model-1. (e) Contribution plot for steric and
electrostatic
interactions GA-PLS model. (f) Plot of observed versus predicted activity by 3D QSAR GA-PLS model. (g) Contribution plot for
steric and
electrostatic interactions SA-PLS model. (h) Plot of observed versus predicted activity by 3D QSAR SA-PLS model. (i)
Contribution plot for
steric, hydrophobic, and electrostatic interactions SW-PLS model. (j) Plot of observed versus predicted activity by 3D QSAR SW-
PLS model.
The steric and electrostatic interaction energies are
The signifcant model with �2 = 0.8499 was com-
10
considered, as International
puted at the lattice points Journal
of the gridof Medicinal
using a methyl
model-1 showed an internal predictive power (�2 = probe Chemistry
0.8267)
compounds (�-axis) setting intercept to zero, the slope of thecharge +1. The
correlation bestbetween
matrix GA-kNN the MFAphysicochemical
3D QSAR model
and
of the a predictivity for the external test set (pred � 2= that
param-
0.7729)
ftted line gives the value of �. has
etersa and
�2 ofthe
0.7663 and pred
biological �2 of for
activity 0.7386 was are
model-1 considered.
of about 77%. The �-test = 45.897 shows the statistical The points
presented generated in GA-kNN MFA 3D QSAR model
3. Results and
signifcance Discussion
of 99.99% of the model which means that are S 1044
in Table (−0.0317,
5. The −0.0317),
contribution chartEof184 (−0.2885,
selected descriptors
the −0.2885),
is and
QSAR studyofwas
probability performed
failure on thiophenyl
of the model C-arylIn
is 1 in 10000. S 931 (−0.0306, −0.0306). Figure 1(e) shows
represented in Figure 1(c). Also, the graph for the
observed
glucoside
addition, contribution
versus
derivatives
the for theirtest
randomization SGLT2 inhibitors
shows confdenceas potential
of ∼99.9% plot of theactivity
three models
predicted for thefor the is
series electrostatic and steric
plotted in Figure 1(d)
antidia-
that the felds,
which
betic agents.
generated Comparison
model of the and
is not random obtained
henceresults
it is chosen respectively, and indicates relative regions of the local
shows good correlation.
indicated
as felds
Molecular felds are the steric, electrostatic, and
superiority
the QSAR model. of Genetic
the genetic algorithm over
algorithm-PLS model theindicates around
hydro- the aligned molecules leading to activity
simulated
the pIC50 =
positive 0.6451 (±0.1584)
contribution of SsCHSsCH 3 count
3 count, + 0.4287 variation in
and SaaSE- phobic interaction energies which are used to develop a
annealing (SA) and
index (±0.0851) T Cstepwise forward-backward
Cl 1 − 0.2574 (±0.0036) LUMO variable the model. For electrostatic feld and steric felds, the
model pIC
for 50
3D =QSAR.
S 1044In(−0.0317,
this study,−0.0317)
3D QSAR−models
E 184
method
showed for feature
energy
that increase selection:
in the values of these descriptors lattice were generated
(−0.2885,by kNN-MFA in conjunction with genetic
is + 0.2789 (±0.0487) SaaSE-index; points generated inSthe
algorithms (GA), −
−0.2885) 931model
simulated are E−0.0306);
annealing
(−0.0306, 184 (−0.2885,
(SA), and stepwise
benefcial for =
�training 26,
the �test =
SGLT2 7, degreeFrom
inhibitors. of freedom
the above = 21, �2 −0.2885)� = 26, � = 7, �
(SW) forward-backward selection methods:
training test 2 = 0.7663, �2 se = 0.3389,
model,= and S 1044
�-test(−0.0317,
= 38.4683, −0.0317)
and predand �2 =S 0.7386.
931 (−0.0306,
0.8499,
it is clear �2 =descriptor
that the 0.8267, �-test =145.8975,
T C Cl contributes�2 se = −0.0306).
0.3098,
positively These points suggested the signifcance of electrostatic
�2 se =inhibitors
to the SGLT2 0.3464, pred �2 = 0.7729,
activity, and pred �2 to
which corresponds se = prop-
count 0.6158. erties as indicated in the ranges in parentheses for
of number of carbon atoms separated from any chlorine maximum
atom by 1-bond distance. Thus, the presence of chloro SGLT2 inhibitory activity. The negative value for E 184
substituents (like in compounds 1–18) would increase means
the that electron-withdrawing substituents in this region are
activity. Descriptor SsCH3 count indicates that increase favorable and would increase SGLT2 inhibitory activity,
in as
methyl group of R position may lead to an increase in shown by the presence of chlorine group in the active
the com-
activity. Its positive value suggests that increasing the pounds. Therefore, less steric and more steric
number substituents
of such carbons will lead to better SGLT2 inhibitors. This were preferred at the position of generated data points
suggests that substituents such as methyl would S 1044
increase and S 931, respectively, for enhancing the biological
the activity. The above results are in close agreement activity
with of thiophenyl pharmacophore. Two data points
the experimental observations, where compounds 10, generated
15, 16, at the position of R around thiophenyl nucleus were
17, and 28–33 at the R position produce SGLT2 steric
inhibitors. points S 1044 and S 931 which indicates that less steric
Molecules with negative coefcient LUMO energy can or
accept less bulky substituents are favorable on this site. On the
electrons more easily than those having high LUMO other
energy. hand, less electronegative groups such as hydroxyl and
The SaaSE-index (∼24%) shows the sulphur atom nitro.
connected The electrostatic blue ball model around R positions of
with two aromatic bonds in the molecule and is the
inversely thiophenyl suggested the electron-withdrawing groups
proportional to the activity. This further suggests that on
the this position benefted potency; this may be the reason
increase in electronegative atom environment adjacent why
to compounds with double bonds at R positions had higher
indicated sulphur atom would result in increase in the potencies than other compounds. In addition, a red
activ- contour
ity. In addition, in agreement with QSAR model, near the position suggested the electron-withdrawing
presence of sub-
more bulky and hydrophilic substituents like methoxy at stituent would increase the activity. Therefore, the –OH
ring at R
R led to an increase in SGLT2 potency. On the other position resulted in signifcant increased activity.
hand, Electron-
more lipophilic halogens like chloro in this X position withdrawing nature of the electronegative chloro atom
retain does
the SGLT2 inhibition activities. The residuals (observed- contribute to the SGLT2 inhibitory activity of the
predicted activity) were found to be minimal and are molecule.
pre- The graph for observed versus predicted activity for the
sented in Table 4. The statistical results of best model series is plotted in Figure 1(f) which shows good
and correlation.
International Journal of Medicinal 11
Chemistry
Table 4: Comparative observed and predicted activities (LOO) of thiophenyl SGLT2
inhibitors.
2D model-1 3D model-GA-PLS 3D model-SA-PLS 3D model-SW-PLS
Com pIC50
Pred.Res. Pred.Res. Pred.Res. Pred.Res.
7.1845−0.1216 7.1847−0.1218 7.1718−0.1089 7.05530.0076
1 7.0629 7.4978−0.0369 7.36790.093 7.12830.3326 7.22890.232
2 7.4609 6.8737−0.0199 6.75650.0973 6.9154−0.0616 6.72950.1243
3 6.8538 7.2319−0.0449 7.07890.1081 7.11220.0748 7.10470.0823
4 7.187 7.25640.0064 7.4543−0.1915 7.24280.02 7.3525−0.0897
5 7.2628 6.94480.0098 6.91210.0425 6.93930.0153 6.9875−0.0329
6 6.9546 7.1464−0.1196 7.0723−0.0455 7.1174−0.0906 7.1653−0.1385
7 7.0268 6.9815−0.0422 6.9644−0.0251 6.91630.023 6.91280.0265
8 6.9393 7.1854−0.0349 7.07460.0759 7.1649−0.0144 7.1761−0.0256
9 7.1505 7.82890.0638 7.86940.0233 7.82650.0662 7.86560.0271
10 7.8927 7.3283−0.0132 7.3729−0.0578 7.3247−0.0096 7.18260.1325
11 7.3151 7.91350.0109 7.9918−0.0674 7.9418−0.0174 7.9356−0.0112
12 7.9244 7.2857−0.0431 7.2498−0.0072 7.3821−0.1395 7.21480.0278
13 7.2426 6.78450.0059 6.7954−0.005 6.7991−0.0087 6.78940.001
14 6.7904 7.21380.0066 7.2525−0.0321 7.2862−0.0658 7.19660.0238
15 7.2204 8.3791−0.0295 8.3875−0.0379 8.34240.0072 8.34460.005
16 8.3496 7.98450.0026 7.9949−0.0078 7.93260.0545 7.96740.0197
17 7.9871 7.1278−0.0883 7.1392−0.0997 7.0734−0.0339 7.0673−0.0278
18 7.0395 7.92430.015 7.9418−0.0025 7.93880.0005 7.91320.0261
19 7.9393 7.92750.1314 8.0692−0.0103 8.0872−0.0283 8.1471−0.0882
20 8.0589 7.29610.0031 7.14910.1501 7.14490.1543 7.23070.0685
21 7.2992 7.5884−0.0278 7.42810.1325 7.51610.0445 7.53190.0287
22 7.5606 7.6978−0.0221 7.59460.0811 7.59880.0769 7.59750.0782
23 7.6757 7.13260.0137 7.13840.0079 7.2864−0.1401 7.11250.0338
24 7.1463 7.09680.0649 7.1948−0.0331 7.12890.0328 7.1799−0.0182
25 7.1617 6.32910.0167 6.32590.0199 6.16430.1815 7.4332−0.0874
26 6.3458 7.1853−0.1313 6.93420.1198 6.97680.0772 6.90870.1453
27 7.054 7.2218−0.0645 7.02020.1371 7.2738−0.1165 7.2684−0.1111
28 7.1573 7.6283−0.0228 7.6163−0.0108 7.60230.0032 7.6132−0.0077
29 7.6055 7.2346−0.0114 7.2458−0.0226 7.2282−0.005 7.2547−0.0315
30 7.2232 7.85790.0486 7.88810.0184 7.81940.0871 7.86580.0407
31 7.9065 7.29820.0071 7.04240.2629 7.19210.1132 7.8928−0.5875
32 7.3053 7.47280.0603 7.34660.1865 7.33080.2023 7.27330.2598
33 7.5331
International Journal of
Carbohydrate Journal of
Chemistry Quantum Chemistry
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